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Alfred Morgenstern: Well, thank you very much to the organizers for the kind invitation and the opportunity to speak here. It’s really a wonderful meeting. I was asked to talk about our experience with actinium-PSMA.

And the whole story obviously began back in 2013, when we first synthesized actinium-PSMA at the JRC in Karlsruhe and did the initial preclinical work. And then shortly after, I started treating the first patients with Clemens Kratochwil and his team in Heidelberg.

And basically, after two years, when we saw a number of sustainable and remarkable responses, we decided to publish the first report on this in 2016, and this became one of our more popular papers. And I'm very grateful, actually, to the JNM that they accepted and published this at that time.

We had actually sent it to the European Journal before, and they rejected it because they thought it was too anecdotal. So actually, the day after this came online, we got a really nice message from Jonathan Simons, who was then President of the Prostate Cancer Foundation. He was very intrigued by these results.

And two weeks later, he came to Germany to sit down with us and discuss the data, really reassuring us that we were on to something there. So this obviously generated a lot of interest in actinium-PSMA, and then targeted alpha therapy in general.

So over the years, we tried to move this forward with a number of partners in the frame of early access or compassionate use programs, and also prospective studies. So basically, since 2014, with Clemens Kratochwil in Heidelberg, we looked initially at those findings, and then some dose de-escalation, and actinium–lutetium cocktail regimens to decrease toxicity.

In 2017, we implemented this at Steve Biko Academic Hospital in Pretoria with Mike Sathekge, really looking at earlier treatment lines and particular focus on chemo-naïve patients. And in the same year, we started in Munich, together with Matthias Eiber and his team, to look at actinium-PSMA post-lutetium-PSMA.

In 2021, the Phase I dose-escalation study on actinium-PSMA-I&T started at Erasmus. And after several years of preparation, initially still with Endocyte, the ACTION study then started at Steve Biko Academic Hospital with Mike Sathekge, later joined by Louis Emmett in Sydney.

So of course, there’s a lot going on in that space now. And Jeremie gave a fantastic overview yesterday about the ongoing clinical studies. So I can really skip that. And we just heard about all the antibody studies that are going on with actinium.

So we got a very nice overview on that too. Basically, one of the initial questions we wanted to address with Matthias Eiber and his team in Munich was: What is the role of actinium-PSMA after failure of lutetium-PSMA?

And in this study, with 26 patients who had been heavily pretreated and all had also undergone lutetium-PSMA therapy, we saw that there is still some benefit of actinium-PSMA. Looking at the PSA responses, there were 65% of patients who had a PSA decline of more than 50%

And interestingly, also a number of patients who initially did not respond to lutetium-PSMA still benefited from actinium-PSMA. However, we saw quite a bit of Grade 3–4 hematologic toxicity in about one-third of these patients, and very significant xerostomia that led to a discontinuation of treatment in about a quarter of patients—likely due to the addition of actinium-PSMA on top of the lutetium-PSMA pretreatment.

So in this patient group, really, the benefits and the risks of adding actinium-PSMA to lutetium-PSMA should be looked at very carefully for every individual patient.

Last year, we were able to analyze the data in 233 patients who were treated with Clemens in Heidelberg in two regimens trying to decrease xerostomia.

One group had a de-escalation regimen of actinium-PSMA monotherapy, starting with 8 or 6 MBq initial dose depending on the extent of disease, and then reducing the dose in 2 MBq steps depending on response. The other group received an actinium–lutetium cocktail.

And actually, both treatment regimens showed very good anti-tumor activity in the patients—more than 50% had a PSA decline of more than 50%. And these are rather poor-prognosis patients. But in contrast to the high-dose regimens, we didn’t have any treatment discontinuation due to xerostomia.

So I think this is really a very good way to go in order to decrease the main side effect of this treatment.

Together with Mike Sathekge in Pretoria, as I said, we were focusing on patients in earlier treatment lines, especially in chemo-naïve settings. In this paper from 2022 with 53 patients who were treated with actinium-PSMA in the chemo-naïve setting, 91% of the patients had a PSA decline of more than 50%.

We are actually in the process of re-analyzing all the data with regards to overall survival, because the median was not reached at the time we published this. And also looking at the long-term renal toxicity, because I think this is a very important question in this group of patients, where you sometimes see very long-lasting remissions.

And this is one example of a five-year complete remission in one of the few chemo-naïve patients that were actually treated in Heidelberg with Clemens Kratochwil.

So looking at this, obviously, we very frequently see Grade 1 and Grade 2 xerostomia, but we don’t see severe hematotoxicity in these patients.

And for the renal toxicity, at the moment, the predictor is really the baseline. So patients with renal impairment at baseline tend to get worse, while patients with good kidney function initially don’t experience a lot of side effects. But we are in the process of analyzing all these data now.

So obviously, last year, we were able to analyze a larger group of patients—nearly 500 patients from seven centers treated in Africa, Europe, Asia, and Australia—looking at safety and toxicity.

And also in this pretty large patient group, more than 50% of patients had a PSA decline of more than 50%.

And the large number of patients also allowed us to look at subgroups. And obviously, previous chemotherapy, previous second-line hormones, or prior lutetium-PSMA were negative prognostic factors, as well as liver metastases, peritoneal metastases, and anemia at baseline.

So to conclude, I mean, actinium-PSMA has really been the game changer for alpha therapy. It doesn’t only offer a new treatment option for prostate cancer, but it has clearly demonstrated the potential of alpha therapy with actinium—and with alpha emitters in general.

As we have seen, a large number of actinium-labeled radiopharmaceuticals are under development. We are still facing a somewhat limited supply of actinium, but the situation is improving. I’m going to talk about that in my next talk. But a lot of additional production facilities are under implementation. So I think the situation will improve.

Thank you.