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Oliver Sartor: Hi. I'm Dr. Oliver Sartor here with UroToday. And I have a special guest, Kambiz Rahbar, who is Professor of Nuclear Medicine at Münster. Very well established in the theranostic field, been involved with many, many, many studies over the years. Welcome, Kambiz. Look forward to your comments today.

Kambiz Rahbar: Thank you, Oliver. Just also want to thank you for the invitation and having me here. So first of all, I would like to thank for the invitation, and here to give you the chance to talk about the final results from the RaLu study, where we looked at the safety and efficacy of lutetium PSMA therapy in patients with prior treatment with radium.

So as you might know, radium is an established alpha particle emitting radionuclide that prolongs overall survival and improves quality of life in patients with bone-predominant mCRPC. Whereas lutetium PSMA is a beta particle emitter which prolongs overall survival in heavily pretreated PSMA-positive patients with mCRPC. To date, there remains a lack of data on the feasibility of sequencing radium and lutetium PSMA.

The objective of the RaLu study was to compile a comprehensive chart review study to investigate the clinical feasibility and safety of sequential use of radium and lutetium PSMA in patients with mCRPC. So data were collected from multiple centers in Germany, and also in Israel for patients with mCRPC who had received at least one radium dose. And in any subsequent therapy line, at least one lutetium dose. The primary objective of RaLu was to investigate the safety and clinical efficacy of lutetium PSMA treatment in patients with prior radium therapy.

The primary endpoint, as I said, was safety. And the secondary endpoints included the incidence of grade 3 to 4 laboratory abnormalities, overall survival, and changes from baseline in serum PSMA, PSA, and alkaline phosphatase levels. There were 198 patients in the RaLu study included, as well as we are going to talk about this data on these patients and look at the safety. We will also look at the different sequences, and also the time between the therapies.

So let us look at the safety. The incidence of grade 3 to 4 laboratory abnormalities measured from the start of lutetium PSMA, up to 90 days after the last dose was highest for anemia, which occurred in 32% of patients, and thrombocytopenia, which occurred in 70% of patients. And something you have to know is half of the patients had already thrombocytopenia prior to starting of lutetium PSMA.

The safety profile of lutetium PSMA was similar irrespective of whether the time between radium and lutetium PSMA treatment was less than six months, or greater than six months, or equal to six months. The safety profile was also not impacted by the order in which patients receive radium and taxane chemotherapy prior to receiving lutetium PSMA. From starting lutetium PSMA to 30 days after the last dose, 78% of the patients had a treatment emergent adverse event, and 25% of patients had a grade 2 to 4 adverse event.

If we exclude laboratory abnormalities, the most common adverse events were dry mouth, asthenia, and decreased appetite. As for the laboratory abnormalities, the proportion of patients with treatment emergent adverse events were similar across the subgroups, which indicates that the time between treatment and the order of prior therapies did not impact the safety profile of lutetium PSMA. Median overall survival for all patients from the start of lutetium PSMA was at 12 months. Median overall survival was similar across the subgroups, ranging from 10 to 12.6 months. And this also indicates that factors such as the time between treatment and the order of therapies prior to lutetium PSMA did not have a large impact on survival outcomes.

So in conclusion, we can say that the results of the RaLu study show that in patients with mCRPC previously treated with radium, lutetium PSMA can be administered safely with outcomes consistent with other published reports. The safety and efficacy of lutetium PSMA are similar, irrespective of the length of the time between radium completion and lutetium PSMA initiation, and the positioning of taxane chemotherapy within these treatment sequences.

So these results provide valuable guidance for optimizing treatment sequencing and decision making in clinical practice. So we can also look at the relevance of the RaLu findings alongside other recent or ongoing clinical trials. So the data of PEACE-3—the end trial was presented at the ESMO. So these findings showed that the combination of radium with enzalutamide was an effective first-line therapy for mCRPC, with significant improvement of rPFS and OS, versus in the group receiving enzalutamide alone.

So both PEACE-3 and RaLu indicate that there is a place for radiopharmaceuticals early in the disease stage. And RaLu has also shown that it is clinically feasible to treat patients with more than one radiopharmaceutical in sequence. So the ongoing AlphaBet trial, which we can see on the right side here, is assessing whether it is feasible to treat patients with radium in combination with lutetium PSMA at the same time. So along with RaLu, these other studies should help to inform clinicians as how to optimally use radiopharmaceuticals in the future.

And hereby a thank you for listening to this presentation.

Oliver Sartor: Yeah, excellent and provocative. I think, first of all, you dispelled the anxiety over giving the radium first and lutetium second. It just doesn't really appear to be a particular issue here. Perhaps even surprising to me was the data with the taxanes. The taxanes themselves really didn't seem to alter that much. So this could have implications fairly broadly in terms of sequential therapy.

Let me move on to the PEACE-3 just for a moment, because I think this has potential large implications. The original ALSYMPCA trial published in 2013 was in an era where the ARPIs were not yet in use. And so, there's always been a bit of a conjecture about how radium and the ARPIs may interact. And then we had the somewhat disastrous study, the ERA-223, which showed a high risk of fracture and no benefit when given the abiraterone. But PEACE-3, now incorporating the bone health agents, has really been—I'll say, a very changing landscape of the perception.

So question number one, how do you envision the PEACE-3 data impacting routine care? Do you think that'll be feasible in the German market? Do you think that radium will have more of a place in combination with enzalutamide going forward?

Kambiz Rahbar: So we look at the PEACE-3 patients. These patients probably do not exist in these numbers as they did a couple of years ago. Because you're giving RPE ARPIs already in the hormone-sensitive settings, so the patients are not ARPI naive at that point. But we still see 30% to 40% of the patients getting mCRPC without having any ARPIs. So I think there is a place for these patients to give enzalutamide plus radium as a first-line therapy in this selected group of patients.

And if we look at the data with RaLu, we can say that we start with enzalutamide and radium, and then they could receive docetaxel, and then receive PSMA therapy. So I think this is a chance for the patients to prolong survival, maybe in completion with all these therapeutics, and longer survival. Which we don't know at the moment, we will find out in the future.

Oliver Sartor: Yes. But I always like the fact when patients have more options. I think that they have the possibility to do better. And sequential use of life-prolonging therapies I think is important. And that's what you've showed here in part.

Now, deviating a little bit into the ENZA-p trial presented by Louise Emmett, now published. And that has some analogy to the PEACE-3. It's an enzalutamide study with lutetium now—PSMA-617 lutetium—instead of the radium. But also, predominantly performed in patients with only ADT monotherapy as their precursor prior to the metastatic therapy state. Do you envision that that could potentially be a path forward for lutetium in combination, or do you think that's going to be requiring additional regulatory approval in that setting?

Kambiz Rahbar: I mean, you are absolutely right. I mean, ADT as a previous therapy is not the real word anymore. But I think, in the future, we will need more data. I don't think it is going to be the path of PSMA therapy as a first-line therapy, and using enzalutamide plus PSMA. But if we look also—we bring PSMAfore data into that decision, these patients had previously ARPI, and then receive another ARPI and PSMA together, and this prolonged RPFS.

So I think combination therapy is the future of any therapeutics, as we have the double or triple therapies already in a hormone-sensitive setting. I think, in the future, something we need is looking at sequential therapies. I think if we have studies with 100% crossover, starting with—whatever it is, it's taxane plus—I mean, versus PSMA, and then with 100% crossover. And then you give the other therapeutic afterwards to look which sequence is going to help more to prolong survival, to prolong RPFS. I think this is going to be interesting.

But I don't think that one of these studies is going to be the only one way to go. So I think it's going to be more complex, more combination therapies, and more sequential therapeutics that can be given. I think we have to be careful, in the future, to give more options to the patients. I don't think it is wrong to start with the one therapy if we know that we have other options in sequence, and they don't impact the survival significantly.

Oliver Sartor: Yes, and I certainly agree. And the bottom line is, this is good news for patients to be able to have more options. And I think this RaLu study has helped to delineate a sequence that was previously a bit unknown. Now, let me flip it around for a second. Do we know anything about the use of radium in the patient with prior treatment with PSMA lutetium? Do we have data and radium post lutetium? I'm not aware myself in any structured data, maybe you are.

Kambiz Rahbar: At the moment, we don't have data on that. We have treated patients with radium after lutetium at our department. So we have seen these patients, but we don't have analysis of these patients in a structured way. So we don't have data currently. I don't think there are other groups that have presented data.

I haven't seen any in the past. So I think this is something we should look at, probably, because these patients exist that have received radium after lutetium. Is the RaLu—other way around is the LuRa. So maybe we should look at that.

Oliver Sartor: Oh, thank you. And I'm just trying to think in a symmetrical way. And then you mentioned the AlphaBet trial, and actually, I think that's a pretty clever idea to be able to put the two isotopes together. Here we're talking about sequence one, while I just ask about the sequence the other way. Now we're going to talk about not sequencing, but combination with isotopes. And my experience—and I'd like to hear yours—is that a lot of patients who get lutetium actually fail in the bone.

That the lymph node disease seems to be a little better controlled, whereas the bone disease is not quite as well controlled as the lymph nodes. And of course, where does radium go? It goes to the bone. It'll maybe be able to augment that activity. What's your theoretical concept about the combination? And then, of course, we are going to have to wait till we see some data. But I'm curious about your thoughts about the combination of a PSMA lutetium combined with radium, particularly for bone-enriched prostate cancer patients.

Kambiz Rahbar: I think this is interesting to look at, because I think we could boost the therapy efficacy. We have two different mechanism of actions. So we have one agent which is only taken up in bone metastasis, and also normal tissue, but in bone metastasis mainly. And then we have the PSMA, which is a targeted therapy to PSMA-positive tumors. So I think we can have an additional efficacy probably. But we need more data, more patients.

I don't think that—if you have selected group of patients, they will have a benefit. And I don't think that the toxicity is going to be very high, or higher than we have in other studies. So I'm curious to see data. I mean, we need a larger group of patients receiving these therapeutics. So the efficacy is going to be interesting.

Oliver Sartor: I agree completely. And I think the toxicity will be manageable. Of course, it can always be a surprise, but we need to pay attention. I appreciate your discussion. And just in summary, we talked about RaLu, and presenting the data that clearly demonstrates the safety, and probably efficacy—got to be a little bit careful on the efficacy—but did not seem to be undue safety concerns with giving radium first and lutetium second.

We broached the topic about the inverse sequence—I liked the way you called it, the LuRa study—which I haven't heard before. I like that. And then, of course, about the combination, which I think we'd all like to see data. So Kambiz, thank you so much for being on UroToday. Thank you for helping to educate our audience on these provocative studies, and appreciate your time.

Kambiz Rahbar: I thank you for the invitation.