Alicia Morgans: Hi, I'm so excited to be speaking with Dr. Neal Shore about the RALU study. Thank you so much for talking with me today.

Neal Shore: Oh, my pleasure.

Alicia Morgans: Wonderful. So the RALU study is a really interesting retrospective analysis, about 130 patients in this analysis, that really looked at the safety and disease related outcomes of patients who were treated with radium, either before or after taxane and then lutetium. So we'd love to hear you just give us a little understanding of this analysis, and then what some of the findings might have been.

Neal Shore: Yeah, I think this is great. This was largely conducted within Germany. As we know, historically, radium and alpha particle, well-documented, level one evidence for life prolonging effects. Very well tolerated, by and large. A 60-second infusion ideally given 28 to 30 days apart, no pre-medication, post medication. You give six cycles. And we see in the SIMCAP trial benefit in both pre chemotherapy, post chemotherapy mCRPC patients. And now we now have PSMA-RLTs and Lutetium 617, the approval of Lutetium 617, also known as Pluvicto in the US, but our colleagues in Northern Europe and other parts of the world, Australia and elsewhere have been using PSMA-RLTs for some time. So this was a very nice real world retrospective analysis of, what happened to patients who were particularly heavily pretreated. On average, I think about four different lines of therapy some had chemotherapy as you say, some hadn't, but then all had previously had radium 223.

So the question that Rahbar and his colleagues wanted to answer was, well, would they tolerate Lutetium 617? And the answer is it looks like they tolerated very well. The vast majority received four cycles, a significant number got five and six cycles, and then overall, the incidence of any kind of myelosuppressive effects was very, very small. So this is an important study in that, granted it's retrospective, it's 133 patients, but it demonstrates that we can continue to think about novel mechanisms of action with life prolonging benefit, ARPI, taxane, alpha particle radium 223, and now beta particle Lutetium 617 with a conjugate for radioligand therapy. So of course, mCRPC, it's a terminal disease for most patients. How can we optimize care? So it's really good to see to Rahbar and his colleagues and their credit that this is achievable. So I really applaud them for doing the RALU analysis.

Alicia Morgans: I agree. And I think it's also important that we see PSA responses, alkaline phosphatase responses, and that seems to be whether chemo is included in the mix there or not. And it's also, as you said, important that we see that safety data as well when we really do want to make sure that we can get every drug possible to patients. And many of the patients who might ultimately receive lutetium in our clinics have had exposure to radium 223 in the past, and we want to make sure that if that's the right treatment sequence for them, that it is going to be safe for them to ultimately get lutetium in the future.

Neal Shore: Well, you raise a great point. As the biomarkers of both PSA and ALP. Historically with radium, we tend to see these nice ALP declines. We've seen in the VISION trial and other PSMA-RLT studies, we see PSA declines to a higher percentage than we do see with radium. Very nice in the RALU study that we saw significant PSA and ALP declines. So that's always a nice thing to have with patients in addition to the safety, in addition to following these patients outwardly to make sure that they're getting the clinical benefit that we all want.

Alicia Morgans: Great. So how do you use this data in your practice? Do you use it to try to understand whether patients may still have the opportunity for lutetium? Are you thinking about it in terms of sequencing and when an opportunity might be there for use of radium versus lutetium and how are you really incorporating this?

Neal Shore: Yeah, I appreciate that. So we had the privilege to be part of the VISION trial and in that they could have received radium, but there was a really, a much longer window preventing them from getting involved and they certainly couldn't get it concomitantly. But now that we're a Lutetium 617 site in the US, I'm getting my patients who have progressed on taxane and ARPI who've previously had or have not, but many who have had radium 223, and I'm a proponent of its use. I think it's as a very good and active drug. And I haven't looked at all of my lutetium patients in great detail, but I think if I had to say at least half have previously had radium 223, I'm not seeing any problems with myelosuppressive effects. The good news on PSMA-RLT, particularly lutetium, is by and large, also very well tolerated, like radium 223. Some different off-target effects. Both require monitoring CBCs, but it's not been problematic for me. I find that the RALU data is supportive of what I've been doing empirically.

Alicia Morgans: Wonderful. So if you had to really give a bottom line for the study and for its implications in practice, what would that be?

Neal Shore: I think the bottom line for me is whenever it's safe and whenever I have that really important shared decision making conversation with patients and trying to do my best to explain to patients what's the risk benefit analysis, I really want to maximize novel mechanisms of action, particularly in patients with CRPC. So I look for that window of opportunity for my bone dominant patients who don't have visceral metastases who've progressed on an ARPI. I actually combine drugs such as enzalutamide with radium 223. I know there's a big important trial that's coming out called PEACE-3 and hopefully we'll see a readout on that sometime in the not too distant future.

I did some earlier trials combining enzalutamide with radium 223, and so I'm very comfortable in doing that. And then when taxane is appropriate or clinical trial and now with the advent of having lutetium very comfortable in that sequence for at the time being given its approval in the US based on the VISION trial. I think that moving forward, the bottom line as I'll continue my bottom line, my expansive bottom line here, we may see eventual approval of PSMA-RLTs, lutetium specifically in pre chemotherapy mCRPC. And I think that there probably will not be a reluctance on my part to think about, again, optimizing novel mechanisms of action alpha and beta therapies. Assuredly the future is bright for other PSMA-RLTs with alpha therapies as well.

Alicia Morgans: Well, great. Well, thank you so much for reviewing this and I think it does inform how we can approach this in our clinical practices. I really appreciate your time.

Neal Shore: Pleasure. Thank you.