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So, this is the chance, as you can see from this case, but you also see the challenges. Because you see it, we've talked about xerostomia and salivary gland toxicity already. You see that salivary glands are nearly diminishing over time, and what you also can say, I have to admit, this is gallium PSMA, and here we have F-18 PSMA. However, what you also see, parallel to the increase in creatinine, is you see a loss of PSMA accumulation in the kidney. So, you see both the chances and the challenges of alpha treatment with this case here. So, what are the principles of alpha versus beta treatment? I think we all know that beta treatment mainly works by single-strand DNA breaks. Beta treatment, in comparison to alpha treatment, so alpha treatment is induced by helium particles, which are much larger than electrons. So, they do much more significant harm and usually what they do is double-strand breaks of the DNA, which cannot so easily be repaired. They have a relatively high linear energy transfer and high energy. Therefore, their effect is not so dependent on the cell cycle.

Their short range also has some advantages regarding potential side effects but also potential disadvantages in the case of heterogeneous disease. So, to understand a little bit better mechanistically the difference and also the differences in the effect of beta versus alpha, you could look at this from a different perspective. If you look at an alpha particle's resting mass, and a beta particle's resting mass, you see there's a four-orders-of-magnitude difference between the resting mass. This is somehow similar if you look at the mass of a Navy gun shell compared to an M16 rifle. So, this is just a very simple illustration of the effect and also the side effects these different types of treatments can do. What was the start of alpha PSMA treatment for prostate cancer? That was, again, coming from the brave people from Heidelberg who, in 2015, after they started with lutetium PSMA, also then explored the use of alpha-emitting treatment. You see here one of the cases they did.

With failure of beta-emitting treatment, alpha emitters can potentially overcome resistance to beta emitters due to the high linear energy transfer, due to the double-strand breaks. And what you see in this case, after a beta-resistant, you see an extensive response after three alpha treatments. So now, the question is, in what space could or should alpha treatment go in castration-resistant prostate cancer? And a number of different publications in the last year explored it in different patient cohorts. And, as similar as for other drugs, the earlier they use it, the higher effect you have. If you look, for example, at the maximum 50% PSA guide, I would like to show you the two sides of the use currently, given the time limit. So, what we do in Munich, we have chosen the late approach. And late approach means that we use alpha-emitting PSMA RT in patients who have failed lutetium PSMA treatment and we use it in patients who have failed all other treatment options. So, this is a publication from a few years ago. Data at that time, 26 patients we have treated so far.

We have treated now around 60 to 70 patients. Results are more or less similar. So what you see in this publication, paralleling what I just told, is that the patients have been heavily pretreated. All of them have had lutetium PSMA, all of them have had at least one AR treatment, and all of them had at least one taxane at that time. So, heavily pretreated patients, the median number of prior pretreatment lines was four, so there was a significant portion of patients who have had all potential mCRPC lines. What have we learned from this experience? So what we have learned is that alpha treatment induces a response in nearly all patients, so any PSA decline we saw in nearly all the patients. We saw substantial PSA decline in two-thirds of the patients. And also, what we saw, that in patients with prior resistance to beta treatment, so lutetium PSMA, in this graph, is outlined by the green bars. So you see here, patients with no or insufficient PSA response after beta treatment and most of these patients also showed a PSA response to an alpha treatment.

However, what we've also seen in this patient cohort, is that the median duration of the response. So the median duration of the PSA response was relatively short with only 3.5 months. Regarding overall survival in this very, very, very heavily pretreated patient cohort, we saw a median overall survival of 7.7 months and we saw that the presence of liver metastasis is a significant negative predictor with a median overall survival of four versus 10 months. This is a typical case of this patient cohort, a patient with prior treatments, Enzalutamide, Docetaxel, lutetium PSMA only two cycles. So he did not respond well to lutetium PSMA. Then went to actinium PSMA, he had significant polyneuropathy. After Docetaxel, was not eligible for another taxane regime. We started treatment with a standard dose, 8 megabecquerels, which correlates to 100 kilobecquerels per kilogram body weight. We saw, in imaging, not big changes between the first and the second PET, we saw some PSA response. We continued treatment, we continued treatment for three cycles. We saw some response after the third cycle. Unfortunately, we had to stop the treatment after the third cycle due to side effects in this patient.

And what you often see is then after the stop of the treatment or sometimes even before you had to stop the treatment, a relatively quick PSA rebound. We've already talked about side effects and I think it is unquestioned that alpha treatment targeting PSMA and therefore also accumulating in the salivary glands has an effect on the salivary gland function. We observe xerostomia in all of our patients and I completely agree with what was said before the lunch break that it's difficult from the CTCAE criteria to really quantify xerostomia because there is in fact no definition for grade four. There is a grade three, really means tube feeding and the discrimination between grade one and grade two clinically is very difficult and weak. And depending on whether it's grade one or grade two, patients can indeed complain about quality of life impairment even if it's only grade one. And what we have seen in our patients is that one-third of the patients discontinued treatment due to side effects. Only a low number we had to discontinue due to hematological side effects.

But a significant number of patients by themselves, despite response, for example like this patient, despite response, on their own wanted to discontinue the treatment given the significant impairment of quality of life. Hematological toxicities in the range, which you would expect in such a heavily pretreated patient cohort with 30 to 50% higher grade toxicities. I would like to shortly switch to the other side of the actinium PSMA story to the experience Mike Sathekge has from Victoria and I really have to say that Mike does a great job in bringing new treatments to patients who otherwise often would have no treatment options. So this is really very honorable what he's doing. And what I've summarized here is his experience in chemo-naive prostate cancer patients. Some of them have been castration-resistant, some of them have been even hormone-sensitive. And this report from 2018 shows a 90% PSA decline, so a substantial PSA decline in 14 out of 17 patients. And by PSMA PET imaging, more than half of the patients achieved complete remission. And this is, for example, one of these cases; there have been no grade three and four toxicities.

And this is one of the patients you see with a very heavy initial presentation and then you see a significant response with undetectable disease which sustains for more than one year at the time of this publication. This publication was also mentioned before during today. There is now, I think since one or two weeks, a retrospective analysis organized via the WARMTH Consortium on the use of actinium PSMA worldwide, and I think seven centers in four countries participated in this. And I would interpret this more as real-world practice because the patients have been significantly differently pretreated. If you look into the different pretreatments they have, you see two-thirds of the patients have had docetaxel, 21, cabazitaxel. If you look in the supplementary data, then you see that one-third of the patients has not seen any chemotherapy. And also, if you look at AR treatment, you see that 39 each has had abiraterone or enzalutamide, and I think it's nearly half of the patients who have had no AR treatment before; one-third of the patients has had lutetium PSMA.

What that publication again shows is that actinium PSMA in principle is an active drug with a 50% PSA decline in 57% of the patients. Median overall survival, and that was already outlined by Johannes, relatively or nearly identical to the duration trial with 15.5 months. What does it mean now? I would say it's difficult to say because we have this really very heterogeneous group of patients. I think we have patients with a low number of pretreatments or even no CRPC treatments who are pulling up the overall survival. And on the other hand, also patients with a lot of pretreatments who are pulling it down. So this is just real-world experience, a mixture of advanced and not so advanced patients. What it shows us again, this publication is that there are different clinical factors which are associated with overall survival. For example, the pretreatment with taxanes, lutetium PSMA, and also the presence of aggressive disease like liver disease and peritoneal disease. More than two-thirds of the patients reported xerostomia. I think the report of xerostomia is always very difficult. There are no detailed investigations in this study on how severe xerostomia was.

It was just a yes versus no question. No questionnaires have been used, and also the impact on quality of life is unclear. It again shows us that the short distance alpha particles travel will make them usually favorable regarding hematological side effects, less than 15% higher grade hematological toxicities. Xerostomia, as I said, is a main issue in alpha, especially in actinium PSMA treatment. And there have been different approaches to limit xerostomia, I would say mainly mechanistic approaches, empiric approaches. None of them so far has really addressed the problem significantly. There have been approaches to stimulate salivary glands, for example, to do sialendoscopy, dilate, irrigate and put saline and steroid into the salivary glands. That was helpful for a certain amount of time. But then after multiple cycles, salivary gland function was reduced and xerostomia was present, so that can help for a short time. Manipulation of PSMA-ligand uptake in salivary glands has been tried by different groups. One, in fact, was done here at UCLA, and a PET study investigating the saturation of PSMA receptors in the salivary glands by the injection, for example, of monosodium glutamate.

It nicely reduced the uptake in the salivary glands, but on the other hand also significantly reduced the uptake in the tumor lesions. So, this is also not a very practical way to go. There are experiments, and I can really say experiments, with temporal blockage of salivary glands by botulinum toxin injection. That means that the salivary gland you inject into. Here, for example, the right side was injected. So, this was pre-injection, this was post-injection. That means that the salivary gland is not working for at least half a year. I've not seen any longer-term outcome data of this where there is less xerostomia present. In this patient, after treatment or not, it would be really very interesting. And then I think also this xerostomia triggered the modification of treatment protocols, and this is something which then introduced the combination of alpha and beta-emitting treatments, so the so-called Tandem protocol. And this is data I received a couple of years ago from Clemens Kratochwil. I think he's one of the main guys driving the actinium PSMA treatment story. So, this is the standard approach.

He was or is using for a long time in Heidelberg, the 8 megabecquerels equaling 100 kilobecquerels per kilogram body weight, and they empirically used different concepts to limit xerostomia, for example, going with a lower dose from the beginning and maintaining this lower dose or starting with a normal dose and then reducing, and also introducing the concept of the cocktail of the Tandem treatment. I think it's too early, or at least from this data, to judge whether there are differences in the outcome. It looks like there is a little bit of a trend that at least this protocol, with the lower activity maintained over time, has a lower PSA response. But I think it's really too early, and the outcome parameters are not strong enough to really judge the value of those modification protocols. In fact, for combining beta and alpha, there are, currently in literature, only two publications which shed some light on it, both from the group in Western Germany.

Here, 20 patients are reported who had an insufficient response to lutetium PSMA and were then put on Tandem treatment, where Tandem in that case means a reasonable dose of lutetium PSMA enhanced by, let's say, half of the usual dose of actinium PSMA. Despite the failure of lutetium PSMA, they saw an interesting substantial PSA decline and also, the median overall survival of 48 weeks or nearly one year. It's at least interesting, I would say. There is xerostomia, which they observed in two-thirds of the patients, which is also in the range that is expected, and a significant response on molecular imaging with 70% of the patients being at least stable or some in remission. So what do we get out of this? I think alpha treatment is a treatment that is highly effective. As always, the earlier the better. However, xerostomia limits its clinical use. I think simple objective measurements for this clinical problem are difficult. Sufficient measures for prevention and treatment are still lacking. Anyway, despite xerostomia, its dissemination is increasing worldwide. If you look now for centers with actinium, you find a lot of centers in different parts of the world.

However, I still think that the role of actinium PSMA needs to be defined. When lutetium is coming earlier, maybe actinium is going then where lutetium now is. Could be an interesting approach. The combination is really only sparse or nearly no data available. The further pathway for me is also unclear from a regulatory point of view because you have to deal, more or less, with two drugs. Are new agents with an improved therapeutic index and with the next step with a higher accumulation in the tumor lesions compared to organs at risk like the salivary gland and kidneys? I've seen some of these agents. Whether they really make the trick, we will see. And as the last slide, I would like to show you how we approach actinium PSMA now in Munich. So this is one page of our joint standard operating procedure for systemic treatment of prostate cancer, which we, from time to time, update between urology and nuclear medicine. So where we currently see, at least in our hospital, actinium PSMA is in what my colleague calls the so-called desperate regime.

So when patients have exhausted all treatments and they can be stratified between PSMA actinium and between platinum-based chemotherapy, we require for both treatments, patients with a fairly well ECOG state. If patients are PSMA negative, clearly this is the place for platinum-based chemo compared to PSMA positive. Prior response to lutetium PSMA, based on our experience now, would more make them eligible for PSMA actinium compared to a non-prior response to lutetium. If it's dominant bone and lymph node metastasis, we often vote for actinium PSMA in contrast to liver, as I've shown you, very poor outcome, or aggressive variants and neuroendocrine prostate cancer. This is something where we would consider platinum or where we would prefer platinum-based chemotherapy over PSMA actinium. Thank you very much.