Kambiz Rahbar: Yeah, thank you, Phillip. I'm happy to be here.
Phillip Koo: So we know independently that radium-223 has an overall survival benefit and we know that lutetium-177-PSMA-617 has a survival benefit. Then in 2024, I believe at the SNMMI, you first presented the RaLu-Study that showed the safety and efficacy of giving lutetium after radium. I know then you presented an expanded cohort at the ESMO meeting. Now you have the LuRa-Study, which was just presented at the SNMMI 2026. Can you tell us a little bit about LuRa?
Kambiz Rahbar: Yeah, thank you, Phillip. I have prepared a couple of slides, which I can share with you. Today I'm going to present data from the LuRa-Study, as you already mentioned, which is a study investigating the safety and survival outcomes of radium-223 administered after prior lutetium-177-PSMA-617 radioligand therapy in patients with mCRPC. Let me first explain the rationale for this analysis. Lutetium-PSMA has become an established beta-emitting radioligand therapy that improves survival in PSMA-positive mCRPC patients, which is already approved by the FDA since 2022. In parallel, we have radium-223, which is an alpha-emitting therapy with proven survival benefit and quality of life improvement in patients with bone-predominant metastatic disease and which is approved since 2013.
However, despite increasing clinical use of both therapies, there is a very limited evidence regarding how to sequence them safely and effectively. As you already mentioned, we have looked at RaLu, which is first radium, then lutetium, and then this is the other way around study which we have performed. Clinicians are still particularly concerned about cumulative bone marrow toxicity because of both treatment-targeted bone marrow, and especially in patients with advanced skeletal disease burden. The aim of our study, LuRa, was to evaluate the feasibility of administering radium-223 after prior lutetium-177-PSMA-617 radioligand therapy.
Data were retrospectively collected at four centers in Germany. A total of 67 patients were included. Inclusion criteria were mCRPC patients previously received at least one cycle of lutetium-177-PSMA-617 radioligand therapy followed by at least one cycle of radium-223 at later stage of disease. We collected those data and did overall survival analysis and used Kaplan-Meier method. Furthermore, we evaluated clinically relevant analysis in three special groups. We looked at time between radium-223 and lutetium-177-PSMA-617 treatment. We looked at sequence of lutetium-177-PSMA-617 and taxane-based therapy prior to radium-223, and we looked also at number of administered radium-223 cycles, less than three cycles and more than four cycles. That was very important to us to look at different groups.
Here we have the total cohort. In total, 67 patients were included in this analysis with a median age of 74 years and the majority had an ECOG performance status of one. Median PSA was elevated at 141 nanogram per milliliter, which shows the advanced disease burden. Nearly all patients had bone-dominant metastatic disease, which is highly relevant for radium-223. Importantly, if we look at the prior therapies performed, a heavily pretreated cohort. Almost two-third of patients had received four or more prior life-prolonging therapies. All patients had prior lutetium-177-PSMA-617 therapy, with a median of four administrations, and most patients had also received androgen receptor pathway inhibitors, docetaxel, and substantial portion had also received cabazitaxel.
We compared patients starting radium-223 within three months after lutetium-177-PSMA-617 versus doses starting after a longer interval after lutetium-177-PSMA-617. Overall, treatment emergent adverse events were common, which is expected in this advanced disease setting. However, importantly, toxicity rates were relatively comparable between both groups. Grade 3/4 toxicities occurred approximately in one-third of patients, regardless of treatment intervals. Anemia represented the most common hematologic toxicity and rates of thrombocytopenia and neutropenia were also generally similar between the two timing groups. Which is important, is no major signal suggested substantially increased toxicity with earlier radium-223 initiation after lutetium-177-PSMA-617. I think this is very important to look at this special cohort.
When we look at overall survival, median overall survival for all patients from the start of lutetium-177-PSMA-617 was 17 months and median PFS was six months. When we look from the start of radium-223, median OS and PFS were five and three months. When we look at the sequencing of taxane chemotherapy before or after lutetium-177-PSMA-617 therapy, what I have to point out here is that mostly the taxane chemotherapy that was given after lutetium-177-PSMA-617 was a second-line chemotherapy with cabazitaxel.
When we look at the overall survival and compared in these two groups, we see that the results are with five versus three months in favor of patient receiving taxane chemotherapy time between lutetium and radium-223. But when we look at the adverse events occurred, it is a slightly higher numbers compared to patients in the lutetium-taxane-radium sequence. When we look at the number of administered radium-223 cycles, the median OS and PFS were higher in patients receiving at least four cycles of radium-223 with nearly similar adverse events in both groups of patients, which is then we have a PFS of four months and six months overall survival compared to two and three months.
In summary, we can say that sequential lutetium-177-PSMA-617 followed by radium-223 therapy is clinically feasible in heavily pretreated mCRPC patients. Safety profile acceptable at this late stage of disease as a salvage therapy, we are trying to prolong survival. This data support flexible sequencing of radionuclide therapies in clinical practice. Here I thank you for the invitation to present our data.
Phillip Koo: Kambiz, that was a great summary. Lots of interesting points here. I think one highlight was the fact that the time interval in between lutetium and radium actually didn't matter. I think a lot of times physicians might think it's better to wait before you start it, but this is showing us that there's no difference whether you wait or not.
Kambiz Rahbar: Yeah, actually, I think in this particular case we have patients at a very late stage of disease. I think these results show that, as you say, we shouldn't wait because these patients are at a very risky situation and we want to prolong their life, so it is important to act.
Phillip Koo: Yeah, you're right. These are heavily pretreated, sick patients, time is very important. Then the other interesting finding is those who received more radium doses tend to do better, which makes sense for multiple levels. But if they get tolerate it, I think it's giving us the message that they should keep receiving those radium doses if appropriate. It's interesting, you're seeing lutetium, Pluvicto, being moved earlier and earlier. Now we see resurgence in data around radium with the PEACE-3 data that was presented last year, so a really exciting time for radiopharmaceuticals. I know the question about sequencing is very, very complicated. What advice do you have for nuclear medicine physicians, urologists, med-oncs who are managing these patients with regards to sequencing?
Kambiz Rahbar: Actually, at the moment we are talking about, as you already said, earlier treatment with radiopharmaceuticals. We had a change after ERA-223 that patients and doctors were cautious giving radium-223. After PEACE-3, we know that in selected patients, radium-223 in combination with enzalutamide can prolong survival significantly. I think at the moment we are at a point that we should say we shouldn't just listen to labels. We have to look intra-individually in patients and select the right therapy for the right patient. For example, at the beginning of mCRPC, we have now radium-223, which is approved, and we have also lutetium-177-PSMA-617, which is approved at that stage. We should look at the patient. We need the scans, PET scan and bone scan, to decide which therapy will be the better therapy for the patient. I think we have to go to patient-centered therapy decision-making and not just look at labels, "Now we give lutetium, now we give radium." I think we have to do it in a better manner. We know now that RaLu and LuRa work both way around and this is the direction we have to go.
Phillip Koo: I think that's great. As you mentioned, the safety piece perhaps needs to be on a case-by-case basis, but it is safe and efficacious. I think you're right, all these therapies, now that they're widely available and across the whole spectrum, not the whole spectrum, but it's our job to personalize the treatment and also make sure patients who are eligible receive both drugs, which again, have been proven to show improved overall survival. Any last comments that you have for us, Kambiz?
Kambiz Rahbar: I think we should look forward. Probably in the future we will have new radiopharmaceuticals. This is just the beginning. We have two approved radiopharmaceuticals for prostate cancer at the moment. In the future, maybe more. I think sequencing these radiopharmaceuticals with chemotherapy and with androgen deprivation therapy androgen receptor targeted therapies is very important, and I think this is the future we are looking at and I'm very excited towards that.
Phillip Koo: Thank you very much, Kambiz.
Kambiz Rahbar: Thank you. Thank you, Phillip.