Zachary Klaassen: Hi, my name is Zach Klaassen, a urologic oncologist at the Georgia Cancer Center. I'm delighted to be joined by Dr. Andy Hahn, who is a medical oncologist at MD Anderson Cancer Center in Houston, Texas. Andy is going to be sharing with us some future perspectives of mCRPC that was recently presented at the Interdisciplinary GU Cancer Forum 2025 in St. Petersburg, Florida. Andy, thanks so much for taking time out of your day to join us on UroToday.

Andrew Hahn: Zach, thank you for the kind introduction and I'll jump right into it. So as you said, the title of this talk is going to be Future Directions in Metastatic CRPC. Here's my conflict of interest statement. The objectives for this talk are to review strategies to target cell surface proteins, to discuss novel strategies to target the androgen receptor, and to understand the rationale for EZH2 inhibition.

So we've entered into a golden era for targeting cell surface proteins and metastatic CRPC. In this figure, on the left-hand side, you can see some of the many different cell surface proteins that are currently being studied and targeted with novel therapies. These include cell surface proteins such as PSMA, DLL3, STEAP1, B7-H3, and KLK2. And it's not just that we're identifying more proteins specific to prostate cancer, but we have a number of different mechanisms of action to target these proteins.

The first and most successful to date has been radioligand therapies. We also have bispecific T-cell engagers. These bispecific engagers are a really promising avenue, but I'm not going to touch on those in this talk. That was a separate talk that we did at the meeting. And then there's also antibody-drug conjugates that can target these cell surface proteins.

The success of lutetium-PSMA-617, or Pluvicto, and the widespread adoption of PSMA PET imaging has led to an explosion in new radioligand therapies, and there have been two broad strategies deployed to develop these novel radioligand therapies. The first is to go back to what's been successful and target PSMA, but with either different alpha particles, so lutetium is a beta-ionizing radiation, we can use alpha particles, or to use new and improved beta particles. The alternative strategy has been to target novel proteins with established beta and alpha particles.

An example of the first approach is shown on the right. So this is the actinium-PSMA therapy that was initially developed by Fusion and then has now been acquired by another company. But what you're seeing here is this is a radioligand therapy that targets PSMA and delivers an alpha-ionizing actinium particle, leading to DNA strand breaks. And what the PSA waterfall plot in the bottom right is showing you is that the PSA50 response in a phase one clinical trial was about 50% and a number of those patients had previously received lutetium-PSMA-617, or Pluvicto. And so this compound is now being studied in a large phase II clinical trial across the US.

There's also been a refresh and renewed interest in antibody-drug conjugates in metastatic CRPC. Antibody-drug conjugates that target PSMA and STEAP1 were studied between 2016 and 2021, but had limited activity and development was stopped at that time. You can see some of the references for these trials in the bottom right. But given this extreme success of ADCs in a number of different other cancers such as bladder cancer, there are now novel ADCs that are doing one of two things, either, A, targeting new cell surface proteins, or B, using advances in antibody-drug conjugate development that have been successful in other cancers to target known proteins.

An example of the first strategy is shown on the right. So B7-H3 is widely expressed in prostate cancer cells. It also has complicated roles in the immune response, and this antibody-drug conjugate that's shown is targeting B7-H3 and releases a chemo payload of deruxtecan. And in the phase I clinical trial with the PSA waterfall plot shown on the bottom right, you can see a PSA50 response of about 30%. And while not quite as encouraging as the prior PSA waterfall plot I showed, this compound has been acquired by a larger company and is entering into a phase III clinical trial.

Now, shifting over to the androgen receptor, many patients who have metastatic castrate-resistant prostate cancer have cancers that remain addicted to the AR pathway and AR signaling even after AR pathway inhibition. And the figure on the far left is showing you the number of different mechanisms that can be deployed to continue to activate AR signaling. The first is you can just amplify the androgen receptor across the cancer cell and use really small amounts of testosterone to trigger AR signaling. The second is you can have mutations within the AR ligand binding domain so that you can use alternative ligands and not need dihydrotestosterone to activate AR. The third is actually to not need ligands whatsoever for the receptor and to have things like the AR-V7 splice variant that are just constitutively active. And last, you can have AR-independent pathways, such as activation of the glucocorticoid receptor, that ultimately target the same shared AR target genes that are downstream.

Now, a number of preclinical and translational studies have confirmed that the copy numbers of AR increased after AR pathway inhibitors, but it's not just AR itself. There's an enhancer in other genes upstream of AR that are also upregulated and continue to drive AR signaling.

Fortunately, in 2025, we now have some novel approaches to target this persistent AR signaling after AR pathway inhibition. I'm going to focus in this figure on two of these. I'm going to focus on opevesostat as well as AR PROTAC, or ligand-directed degraders. So what is a PROTAC or a ligand directed degrader? It has three different components to the drug structure, and these are a totally new class of drugs. The first is you have a ligand for a protein of interest and it's linked to a ligand for an E3 ligase. And so when it goes into the cell, it binds to the protein of interest, for us this is going to be the androgen receptor, and then it creates a stable ternary complex when it binds to the E3 ligase and puts the E3 ligase in close proximity to the protein of interest, resulting in ubiquitination and ultimately proteasomal degradation and destruction of the protein of interest, AR.

There have been three different AR degraders developed to date. The first two were from Arvinas. The first one, to the best of my knowledge, is not further being developed. The second one, ARV-766, has been licensed by another company and is currently being studied in phase II clinical trials.

This BMS compound, 986365, was studied in a phase I clinical trial that we'll go over here. So this has been published, it was published at the end of last year. And what you can see in the PSA waterfall plot on the left is that, yes, this AR ligand-directed degrader does have most pronounced activity in patients who have ligand binding domain mutations where we know that they continue to be addicted to AR signaling. But there are many patients beyond that in the ligand binding domain wild-type group who continue to benefit from degradation of the androgen receptor. And then what the Kaplan-Meier figure on the right is showing us is that patients who did not receive prior chemotherapy seem to benefit the most. Taking all of this into account, there's an international phase III clinical trial that's actively enrolling called the rechARge trial, evaluating this AR degrader from BMS against investigators choice of docetaxel or a second AR pathway inhibitor after a prior AR pathway inhibitor.

Now, shifting over to targeting CYP11A1, abiraterone inhibits CYP17A1 and improves survival across advanced prostate cancer. Because of that success, the question has become can we inhibit further upstream on the steroidogenesis pathway and inhibit CYP11A1, which opevesostat is doing, and improve outcomes? This compound opevesostat was initially studied in a phase I/phase II study where it was given with dexamethasone to replace cortisol as well as fludrocortisone to replace mineralocorticoids, because in about one of three patients adrenal insufficiency was observed. This was a common side effect from inhibiting steroidogenesis of the adrenal glands so high up. But what you can see in the PSA waterfall plot on the right is that there was activity of this drug in all comers, with a PSA50 response of about 38% in the top figure. But then when you go down to the bottom figure and you focus only on patients who have mutations within the androgen receptor and are likely addicted to AR signaling, you see enriched responses with the PSA50 response of 53%. And this has led Merck to open two phase III clinical trials that are currently actively enrolling across the globe.

All right, so we're going to finish up quickly with EZH2 inhibition to augment AR pathway inhibition. So in the early 2000s, Arul Chinnaiyan in his lab showed that EZH2 was overexpressed in metastatic CRPC. In the 2010s, a number of different preclinical and translational groups showed that upregulation of EZH2 plays a role in lineage plasticity. And then in the early 2020s, there have been multiple early-phase clinical trials evaluating EZH2 inhibitors that have been negative. And that leads us to mevrometostat. So mevrometostat is an EZH2 inhibitor, and you can see on the far right that it is thought to restore sensitivity to AR pathway inhibition, hopefully prevent lineage plasticity into a neuroendocrine prostate cancer state, and ultimately result in turning on tumor suppressor genes' transcription.

Dr. Schweizer and colleagues presented this data at GU ASCO in 2025, and what you can see from the phase II randomized clinical trial of patients who were basically first-line metastatic CRPC, after receiving ADT plus abiraterone, they got randomized to either enzalutamide alone or mevrometostat, the EZH2 inhibitor, plus enzalutamide, and the combination significantly reduced the hazard for disease progression by 50% compared to enzalutamide alone. So this was pretty noteworthy and has ultimately led to phase III clinical trials that are opening up now.

So in conclusion, there are many novel therapies in development to treat men with metastatic CRPC. Novel radioligand therapies targeting new cell surface proteins or using alternative radioisotopes are in late-stage development. And there are new ways to target the androgen receptor that are being developed for metastatic CRPC, and we're likely going to see these therapies forward into the metastatic hormone-sensitive space soon. Thank you.

Zachary Klaassen: Andy, great presentation. There's so much to jump off on. I think the organizers of the meeting certainly maybe did a little discredit having to talk about future of mCRPC in 10 minutes, but great job. The last 5 years with radioligand therapy have just been incredible. I anticipate the next 5 will be even more exciting, especially with Pluvicto moving up in the disease space. Out of the new agents that are coming in the RLT space, what's got you the most excited? What do you think has got the chance to be the biggest impact?

Andrew Hahn: Yeah, thanks, Zach. I think you make a really good point that we are going to get more and more space between the time that patients receive first RLT and the potential to receive a second RLT later in metastatic CRPC. And that space is going to make it easier to deal with side effects of multiple RLTs. That being said, the actinium-PSMA compound that I highlighted from initially developed by Fusion, and I think it's AstraZeneca now owns it, but I think that's really encouraging. We have that open here as a phase II clinical trial. It has activity after lutetium PSMA. It's an alternative radioisotope. So it's the one I'm most excited about. I think the limitation that we're all going to have to watch really closely is shared toxicity by targeting PSMA at multiple time points. And the question is if alternative proteins will reduce that shared toxicity.

Zachary Klaassen: Yeah, absolutely. And you give a great highlight of some of these novel targeted agents. I think there's so much coming down the pipeline, different mechanisms of action. Which one do you think is the closest to potentially making an impact? I know there's a lot of phase IIIs going on. What's your hunch as to who's going to be that next big player?

Andrew Hahn: Okay. You're right, there's a bunch of phase IIIs that I covered, and I always tell patients, "In the last 6 months to a year, it's become a really exciting time to be an investigator in prostate cancer. There are really cool novel compounds coming down the pipeline in phase III trials." That being said, my bias is I think the AR degraders are really cool.

Zachary Klaassen: Yeah.

Andrew Hahn: I think that patients and providers are really excited about an oral pill they can take after the cancer has become resistant to an AR pathway inhibitor. I think if we could extend the amount of time that patients can derive benefit from oral AR-targeted therapies, it's going to do a lot to improve quality of life and outcomes for our patients. So that's what I'm most excited about now and I really think we're going to see those actually move forward over time as well.

Zachary Klaassen: Absolutely. Great discussion, Andy. Really appreciate you joining us. Any final thoughts? Anything we haven't hit on that you want to leave our listeners?

Andrew Hahn: The one I have to just mention is that, I shouted it out at my talk, but I did not touch upon bispecific T-cell engagers at all.

Zachary Klaassen: Sure.

Andrew Hahn: There's a lot of really cool stuff happening there. Probably a whole other discussion, but things to pay attention to are also going to be those bispecific T-cell engagers.

Zachary Klaassen: Yeah, well said. Andy, thank you so much for joining us on UroToday and taking time out of your busy day.

Andrew Hahn: Thank you, Zach.