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Alicia Morgans: Hi, I'm so pleased to be here with Professor Kambiz Rahbar, who is the head of nuclear medicine in Groener, Germany, and a professor of nuclear medicine in Münster, Germany; here to talk to us today about the RALU study. Thank you so much for being here, Kambiz.

Kambiz Rahbar: Thank you. Thank you for the invitation. I'm also happy to be here.

I'm going to introduce the RALU study, which was presented at the ASCO GU a couple of weeks ago, and we presented a post hoc analysis of the RALU study, which looks at the time interval between radium and lutetium-PSMA treatment, and the effect that it has on the safety and effectiveness of lutetium treatment.

So radium and lutetium-PSMA are both used to treat prostate cancer and its metastasis. Radium acts as a calcimimetic and is preferentially taken up in osteoblastic bone metastasis. It therefore selectively targets bone metastasis. In contrast, lutetium-PSMA can be used to target both bone and visceral metastasis, providing the target on cancer cells expressing the prostate specific membrane antigen.

Radium and lutetium-PSMA have both demonstrated overall survival benefits, and also acceptable safety in patients with metastasized castration-resistant prostate cancer. The safety profile of radium is similar to that of the placebo, and rates of myelosuppression are low.

And data from the VISION trial demonstrated that lutetium-PSMA had a similar benefit in patients who had previously received radium, compared with those who had not. And furthermore, data from the observational studies have suggested the feasibility of using lutetium-PSMA in patients who have previously received radium.

The RALU study is a multi-center retrospective medical chart review of patients with mCRPC. The question RALU set out to ask is whether it is safe to sequence two radionuclide therapies, an alpha and a beta emitter in patients with mCRPC. RALU looks at the safety and effectivity of lutetium-PSMA in this patient cohort.

The objective of this analysis was to assess the safety and survival outcomes with lutetium when treatment began within six months after radium treatment, compared with those with six months or more. In particular, is it safe to give patients lutetium-PSMA therapy within six months after receiving radium-223 treatment?

So data that we can see here are shown for all patients in RALU, as well as for patients who receive lutetium within six months and of radium, and patients who received radium six months or more after radium.

The baseline demographics and clinical characteristics of these patients were similar between the groups receiving and at different time intervals. And if you look in patients with less than six months or more, a higher median PSA level was shown, and around 60% of patient had an ECOG performance status of one with the remainder of having an ECOG status of two, and proportion of patients with visceral metastasis was similar between the two groups.

So patients had received a variety of life prolonging therapies prior to starting lutetium-PSMA. Per protocol, all patients had received radium-223 in the history. A higher proportion of patients in the six months or more group had received at least four prior life prolonging therapies, compared with those where the time interval was less than six months. The proportion was 64 and 40%.
Around 80% of the patients with a time interval of six months or more had received five or six radium injections, compared with the other group, around 60% in those where the time interval was less than six months.

So if we look at toxicity, the incidence of grade three to four laboratory abnormalities measured from the start of lutetium-PSMA up to 90 days after the last dose were similar between the groups, and was highest for anemia and thrombocytopenia. From a starting lutetium-PSMA to 30 days after the last dose, 71% of the patients who received lutetium within six months of radium, and 82% of the patients where the interval was six months or more, experienced a treatment emergent adverse events of any grade.

In contrast, patients who received lutetium within six months of radium had a higher proportion of grade three to four adverse events, than those where the interval was six months or more, with the proportion being 36 and 24%. Excluding the laboratory abnormality, the most common adverse events were dry mouth, and nausea and fatigue.

The median overall survival for the entire group was 13.2 months. Median overall survival outcomes were similar in the two groups, in the time intervals being 12 months in the patients with an interval of less than six months, and 13.2 months in the groups with six months or more.

Looking at a response, the best PSA response during lutetium treatment were also similar between the groups. Also, a slightly higher proportion of patients had PSA declines of at least 10, 30, and 50%, in patients with an interval of less than six months. Difference has been best alkaline phosphatase responses, at least 30 or 50% are more pronounced between the groups, with a higher proportion of patients with an interval of less than six months having declines in alkaline phosphatase, compared with the group where the interval was six months or more.

So in conclusion, we can say that the data shown here showed that treating patients with lutetium within six months of completing radium was clinically feasible and well tolerated. And also, the total data of RALU shows that giving two different radionuclide therapies in patients with metastatic castration-resistant prostate cancer is safe and tolerable, and also effective. Thank you for this sitting.

Alicia Morgans: Thank you so much for that. I think it's really important as we think from a clinical perspective about the timing of lutetium and radium. And of course, these are both very different in terms of alpha being one, radium's an alpha particle, and lutetium obviously, a beta emitting therapeutic. So I'm just wondering from your perspective, this data does not necessarily comment on anything other than the general safety of these sequences, but are there questions that remain in your mind as you think about these drugs, in terms of which one needs to go first or second from a safety perspective?

Kambiz Rahbar: I don't think the sequencing is very important, because we are doing already the other way around, giving lutetium-PSMA first, and then patients, when they get progressive, and they have a bone dominant disease, we give radium if they have no other options. But at the end, the question started at the time that Pluvicto was going to be approved in, especially in the United States, and people ask, "Can we give two different radionuclide therapies?" Because in Germany we have long year experience with radionuclide therapies, I would say 20 years plus. And this is what is new, completely new in the United States. And the oncologist especially, who decide these therapies, had these questions to be answered. So we tried to give these answers using this multicenter data. So I think this is very interesting for the people, that they can give two different radionuclide therapies. We don't have data on radium after lutetium at the moment, but I think this is the other way around. We have the RALU and LURA is coming soon.

Alicia Morgans: Oh, that's great to hear that your team is continuing to work on that.

Kambiz Rahbar: Yes.

Alicia Morgans: Now, one thing that I think we should just make sure of, because I think one of the questions that remains is really, all of the patients who had their radium and then received their lutetium, regardless of which group they were in in terms of the timing, we would assume that they had recovery of any cytopenias that may have existed because of their previous radium.

Kambiz Rahbar: Yeah.

Alicia Morgans: Does your group have, what are the thresholds that your group is normally using? Because this is something that still, I think, has not been defined in our clinical practices, and it's something that we are going to want to make sure we achieve before we do go from one of those radiopharmaceuticals to the next.

Kambiz Rahbar: Actually, we have the EANM, European Association of Nuclear Medicine, and SNMMI practice guidelines for lutetium-PSMA therapy. And the threshold we use for giving lutetium are the same. And this is, for example, for platelets is 75,000, or for white blood cells is 2.5. And for hemoglobin, we don't look at, there is no threshold. If the patient need a transfusion of red cells, red blood cells, we give them transfusion. We don't stop the therapy, or we don't give the therapy because only of anemia. Anemia is a symptom which we can treat with transfusions.

Alicia Morgans: Wow. I think that's really, really encouraging. And I know that there are teams that are working to put together a US perspective on this as well, with some of the Nuclear Medicine Society team members. So I'm really, really hopeful for that, because anemia can also be caused by progressive prostate cancer.

Kambiz Rahbar: Yes.

Alicia Morgans: And certainly, controlling the cancer can sometimes actually even improve the blood count.

Kambiz Rahbar: Yes. Sure.

Alicia Morgans: This is good. This is very important. So wonderful. So if you had to give a concluding thought or a bottom line on this particular study, which again, thank you for doing this work, because the RALU study is absolutely so important for our clinical practice. What would your summary be?

Kambiz Rahbar: At the end, we can say that radionuclide therapies are at, all of them, is it radium or lutetium, are opening a new door for new therapeutics for prostate cancer patients. I mean, we have the systemic therapies of anti-androgen therapies or new access with apalutamide, enzalutamide, or whatever. But we have the radionuclide therapies that are additional options, or complimentary options. And I think in the future, we will have new therapeutics helping the patients and prolong their life, I mean their survival. So we are all here for helping the patients. So I mean, we are working on new ready pharmaceuticals for cancer at all. So the future is bright for nuclear medicine, and it's going to be a nuclear oncology, I would say. I wouldn't call it only nuclear medicine doing diagnostics, we are doing therapy and oncology, so it's a new era beginning now.

Alicia Morgans: Well, I certainly love that. The future is bright-

Kambiz Rahbar: Yes.

Alicia Morgans: ... always in nuclear medicine, right? And in nuclear oncology, I should say. And so again, thank you so much for this, which really gives us some data that can allow us to think about using multiple radiopharmaceuticals in a safe manner for our patients. Ultimately, we really do want to get every treatment option to those patients that we possibly can, and of course, we want to do it in a safe way. So thank you so much for your time and for your expertise.

Kambiz Rahbar: Thank you for your invitation.