Alicia Morgans: Hi, I'm so excited to be at APCCC 2022 in Lugano, Switzerland, where I have the opportunity to talk with Dr. Neal Shore, who is a CMO Urology at Genesis Care. Thank you so much for talking with me.

Neal D. Shore: Great to be with you.

Alicia Morgans: Wonderful. So, I wanted to speak with you a little bit about the changing landscape in metastatic castration-resistant prostate cancer where we've had the recent approval of lutetium into that space. Now I think we find ourselves trying to figure out how to best order everything, especially in the setting of perhaps some triplet therapies coming in the metastatic hormone-sensitive disease setting. How do you think that through?

Neal D. Shore: So, it's a great advance that we have the approval of PSMA-RLT now with lutetium-617, most recently, based on the VISION trial. This opens another novel mechanism of action, theranostics. It adds to taxane therapy, androgen receptor pathway inhibitors, PARP inhibitors, and in the US two different immunotherapies Sipuleucel-T as well as the MSI high tumor agnostic indication for pembrolizumab and the radiopharmaceutical radium-223. So now we have the proverbial embarrassment of riches. We have data, almost eight different trials, demonstrating the importance of combination therapy for mCSPC patients, couplet and triplet therapy if we look at ARASENS now and PEACE-1.

So, I think, for my urologic colleagues, first and foremost, for the vast overwhelming majority of patients with mCSPC, low volume or high volume, monotherapy is no longer acceptable. And then, I'm not a big proponent of sequencing AR pathway inhibitor drugs. I believe in the importance of exposing patients to as many novel mechanisms of action as possible because mCRPC or resistant disease is still a lethal disease for most patients so we get life prolongation. We can arguably hope to have preservation of quality of life and avoid overlapping toxicities by invoking correct judicious sequencing and or combination. So now with PSMA-RLT or the burgeoning class of theranostics, so, so important, for urologist, and medical oncologist, and radiation oncologist, nuc-med radiologists to work together. The multidisciplinary team is important now as it's ever been.

Alicia Morgans: Well, I definitely agree with that, and especially as you said, with radioligand therapy, and we've had some experience with radium doing that over the past decade or so. It's been, I think, really, really exciting to use that agent and have just not only a different mechanism of action with life-prolonging therapy, but also a tolerability profile that has been, I think, a good one. So where does radium fit into this mix when we have now lutetium-617, but we also see new radiopharmaceuticals coming down the pipeline?

Neal D. Shore: Yeah, I appreciate that question very much. In fact, that's one of the topics I'm addressing at AP triple C in 2022. I think that for many of our colleagues, not only in the US but outside of the US, there's been a concern about combining radium, for example, with abiraterone, the negative consequences of that in the ERA-223. We all await the PEACE-3 trial, which is a concomitant use of radium with enzalutamide. But as you said in your question, we have almost a decade now of data demonstrating the safety and tolerability, starting with long-term analyses from the pivotal registration trial known ALSYMPCA. A large trial, a registration trial that we looked at real-world data globally of over 1400 patients called the REASSURE study, and it really demonstrates the excellent safety and tolerability of radium.

It's very simple to give. It's a one-minute infusion. There's no premedication, post medication. There's very liberal precautions regarding safety measures and any sort of caregiver involvement. This is not necessarily so with the PSMA-RLTs, they're more stringent, there's more involved, there's some structural issues in terms of the implementation. We also have data, small early phase data, that says giving radium to patients, and then subsequently lutetium-617 appears to be safe. There's some early phase studies that say it actually by sequencing these two novel mechanisms of action, we actually can prolong survival. We need more phase three prospective data to confirm this. But I would encourage my colleagues, it's really not a binary one versus the other. Right now, lutetium-617 is approved, FDA approved in mCRPC, post-NHA and taxane, whereas radium-223 is approved in a pre-taxane and post-taxane in mCRPC.

Alicia Morgans: Absolutely. So obviously the indication, the approval of the label, these are different things, but to your point, radium's an alpha particle, lutetium's a beta, we have a different target. So radium is really sort of taking the place of calcium in the bone matrix and there then really giving off that alpha particle, whereas obviously lutetium is PSMA targeting, so it's hitting bone and soft tissue. So these are very different even though they're both radiopharmaceuticals. And interestingly, and importantly, to your point as well, the VISION trial allowed patients who had previously had radium into that study. They just required that patients be at least six months out.

So, I think the safety is pretty clear from my perspective, and I think that giving the opportunity for patients to have access to all of these different mechanisms is going to be important. One thing that I do think about though, as I'm trying to sequence these treatments as well as things like cabazitaxel and prior docetaxel, is supporting the bone marrow because these agents can cause cytopenias, and that can be a cumulative effect in some patients. How do you best think about supporting patients from a bone marrow perspective when you're trying to work all of these in?

Neal D. Shore: Yeah, that's a very important concern. So the RLTs, the PARP inhibitors, the taxanes, or radium, all have potential myelosuppressive effects. So, the bone milieu, the bone micro environment, the bone compartment could ultimately be a rate limiting factor in patients not being able to receive therapy. And in addition to the amount of tumor burden, the amount of marrows replaced by the tumor itself and even arguably other exposures, radiation exposures, etcetera. So this is a very, very important concern. So I don't think there's any simple answer to it. We want to make sure, number one, that almost all of these patients receive a bone protective agent either in the form of zoledronic acid or denosumab for all of these agents, particularly when there's bone metastatic disease. Additionally, I think there's some burgeoning data on just the importance of exercise, perhaps. That's going to at least cut down on fractures. Don't know that it'll necessarily increase red blood cell, or white blood cell production, platelet production, and avoid cytopenias. But we do have to be very cognizant of this right now as this could be an ultimately rate limiting variable.

Alicia Morgans: I agree. Well, we'll continue to think about that and investigate. And in the meantime, I so appreciate your expertise and your comments today.

Neal D. Shore: Thank you.