Initial Experience with Actinium- 225 PSMA in Advanced Prostate Cancer - Machaba Michael Sathekge

December 29, 2019

Mike Machaba Sathekge, MD, PhD presents on the power of medicine, specifically targeted radionuclide therapies and the use of actinium-225 in advanced prostate cancer.  Targeted α-therapy with 225Ac-PSMA-617 although still preliminary, has demonstrated strong potential to significantly benefit advanced-stage prostate cancer patients. He discusses the initial experience with 225Ac-PSMA-617 in a developing country, as one of the first groups to provide this therapy. 


Mike Machaba Sathekge, MD, Ph.D.,  is a Professor and Head of Nuclear Medicine department at University of Pretoria. He is Chairman of the Medical Research Council of South Africa. Mike is at the forefront of the specialist training; hence he was honored by being elected as the President of the Colleges of Medicine of South Africa (National Specialist Examining body for all disciplines). Internationally he is the President International Society of Radiolabeled Blood Elements (ISORBE) and past secretary-general of the World Federation of Nuclear Medicine and Biology (WFNMB). He has introduced several technologies in South Africa. Mike's research efforts in advancing molecular imaging and developing clinical applications have contributed to the clinical and physiological studies on the role of PET/CT on patients suffering from HIV/AIDS and tuberculosis. Prof Sathekge has also introduced peptide receptor radionuclide therapy and peptide radioligand therapy with 68Ga and 225Ac and 177Lu in South Africa and Africa.
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Mike Sathekge: Thanks for the introduction. So I'll try and speak about what we are doing with actinium in South Africa and, of course, I would like to acknowledge the people that have made it possible: obviously the JRC EU and the group in Heidelberg, and of course our group in South Africa. I think it's important as we go into this to speak about the power of medicine in specifically targeted radionuclide therapies. Very powerful, but it's really, (0:46 inaudible) as Chandler has said before. We used to have things that were not effective. Now we've got something that is very effective, but that being effective is actually very dangerous as well. We've got to handle it very well. And so that's how we really have to have systemic approaches into this and see how the matters are going to go forward. So, of course, this diagram had been shown to you all several times, but clearly we've got to go and try and see what we are doing with this situation of the metastatic situation, and to prevent patients from demise.

Why is this a problem? There are several drugs that are novel, very many of them and very excellent drugs. But we really need to know that, obviously, we cannot settle with the overall survival of three months because these drugs are very expensive as well. So we really need to do something. And that's really the question, why we are here? And courtesy of Rod Hicks, when we speak of cancer, clearly we have not been considered. There had been various arms, and clearly then this is the time to obviously include the radionuclide therapy. But how do we phase it in so that it becomes part and parcel of the routine management and not as a service provision to people? So, of course, this was conceived there as one has said and we are happy about how it is going to work. And thanks to, obviously the references of this.

So now based on this, our aim was to see what can we do with actinium to evaluate the therapies to our patients. I have to really declare outright that in our cohort of patients, all of them had ethics approval. That's to agree that indeed this is experimental. This is something that will obviously leave severe side effects. And this is something that, of course, we still have to see how it'll work, but we think it may improve their quality of life based on what has happened. And these patients had, of course, several options that were denied to them because they didn't qualify or they refused those options. So no patients were coerced. So it is the patient that clearly wanted to have another alternative and that's very important to make it clear that this is how we select our patients, of course.

And then, of course, the inclusion would include all the other things that are there for lutetium, obviously, the scan has to be positive, and the bloods have to be within the normal limits. But I have to say some of our patients were having a very terrible ECOG because they didn't have alternatives as I have said. And of importance is that we were looking mainly at patients that had diffuse skeletal metastasis and then those that refused chemo or unfit for it, and even those that had resistance to lutetium. And that's how it has gone to us. So the method of course, as I said, we had to obviously inject gallium to select them. We had 58 patients to which we could look at, but then 43 were the ones that at least had three cycles by this time that we could be here. And there are others that have got single sessions for similar injections.

So how do we go about injecting and doing this patient? Obviously we include them, and then we start with a dose of around eight MBq. And then of course in between, we obviously will be doing the scan because obviously we need to know what is happening, especially that it is experimental. And then clearly we reduce the dose, we deescalate as it goes. But I didn't write the specific amount of the MBqs because we personalize based on the scan and based on the results as well of the PSA and the clinical outcome. So each patient will have a different dose, but we don't go up, we go down on what the doses will be. We can give from one to six at least, but of course, with a patient that has had nothing, we ended up mostly at three but some of them that had had chemos and lutetium, we had gone up until six sessions. And then, of course, this is how we actually would work out. There are specific doses, but at least as a guide, we have also started with some of the patients at 10 MBq but we obviously cascade down maximizing the fact that the first dose is the one that is the most effective one that we should have.

Of course, all of the results, our patients were relatively smaller. As I said, I dealt with those that have three cycles and then most of them had bone metastases because obviously, they're late patients presenting and then some had nodal disease and then visceral metastasis. Like the previous speakers, we hardly had observed no changes or limited side effects in terms of the bloods as you can see with the platelets, white blood cells, and the hemoglobin, obviously based on the fact that we expected from the alpha that it really is confined within the tumor and not going beyond and that's to be expected.

Then, of course, the liver is the same as well as the renal, there wasn't much of a problem. But clearly, like anyone else we did had a problem of 32%, a little bit lower perhaps than the Heidelberg cohort and that probably could be the de-escalation that we are speaking about that, in fact, it has been helpful to actually deescalate and we still have to see. Yes, we are, as well, I've seen that with a Botox situation, but we have tried the patch and we're still looking at the patch on some of our patients, but also on the imaging, but we don't know if really will yield, and from what we've heard from the other speakers, it doesn't look like there's much hope in terms of those other interventions as yet except perhaps for the de-escalation. That might be very helpful.

So now the response, if you look after one cycle, usually with the lutetium, you'll have around 40 and in the study of Hofman that they show around a lower number of patients that have had a decline of more than 50 with one injection. We have had more. And then, of course, when we followed those patients, as you can see, most of them are almost having an even better response of the PSA decline. And of course, that correlates with their scan. So this is great. But, of course, when they stop to not respond well at the beginning, of course, it really keeps on being that situation. And this is good that we really could have that this number of 77 of patients that actually had 50% at the first go.

Of course, looking at the three groups that we have had, the better group where these two, the chemo-naïve and the treatment-naïve, but the post-chemo obviously they also have responded well and they have had lutetium, but clearly, just to justify and put a disclaimer clear that this patient had were treatment-naïve, yes. You could argue that they would respond to anything but surely those are the patients that chemotherapy was denied of them and they were not going be fit for chemotherapy. Yes, and they didn't also qualify for radiation therapy. So in that way, even if you could argue that they could respond to anything, they responded well to actinium pleasantly.

And as I have said, the PSA was there, but the control of the bone pain was something excellent. And this is something remarkable that really we have to remember, that if you've got a bone pain, if you relieve that, that's something we have to really look at, of course. So this actually tells us about theranostics, which is a wonderful thing and we really have displayed it clearly that double-stranded break, it's really important you really within a single injection go from a higher PSA and to a lower PSA with really good results. And we think of course we have to tag (8:24 inaudible) our patients very well in that situation.

But now is this result sustainable? Of course, you can see clearly, as you can see the remission for that patient that I've shown, at least it's over a year now that this person is still in the same situation, which can speak to the effect that indeed DNA double standard is something that is real with this and we have to handle it well. Of course, you do have disappointments. This person has had chemo, lutetium, initial response, but of course, deteriorated and demised in February this year. But we have to say that post-lutetium resistance, we have at least given him 10 months of joy that he could at least live and do something. So that is also not to be discounted as well... So this was supposed to be a movie, but nonetheless it's not playing.

So after two injections, another patient that had responded well. This is a very fantastic patient who actually could do nothing and then of course really a super scan almost, depending on what definition you utilize and this person is well and clearly that is sustainable of these results. As you can see, post when we are started with him in July, and we think we will still be looking at this patient and we will see how they carry on, but indeed we are convinced that this is really good results and that the remission will be long. This person, just to show that you can do also in the interim, has a good analysis. You can see that ECOG was terrible and then as you can see the diffused skeleton that was involved as well. Another one, and then you can see with a PSA of over 2000 and coming down and in the interim as well, you can see clearly that especially with the first injection as I have said, that these people are really likely to respond very well.

So what one is saying is, this is something we have to really now look forward and look at it carefully, and we have to work together. Otherwise, we lose the fish, all of us, if you really don't work together. But clearly, as a nuclear physician says, well we cannot be service providers. It's about time we have to be nuclear oncologists and know how to deal with the mets, and then how to deal with the pains and not refer everything to oncologists. And even if the possibilities of combination therapies amongst ourselves, surely we cannot claim to be having that skill, especially our radiobiology has to actually be upscaled and that will actually help us a lot. And of course, if we do so, then we can actually ask our colleagues that we really have to come earlier before the chemotherapy in many patients.

And then of course to conclude, one is saying that with our early lessons we have seen now that there is good tumor shrinkage. There is symptomatic relief and quality of life, and obviously, the biomarker also states that. There's hardly any renal, liver and hematological toxicity. Yes, we do have xerostomia but all of us can come with a solution. We think de-escalation is something that will help a lot, and clearly we have to obviously select our patients where the indications have to be very thorough and look at the extensive bone mets and diffuse mets as the indication, and clearly not something to compete with lutetium but to compliment lutetium in that way. And of course we also, in that way, need a prospective Phase I, Phase II trial to actually validate these results. But in so doing we also are going to start to think about the production of actinium, especially the cyclotron based methods so that we all benefit from this. Thank you.

Speaker 2: Excellent talk, thank you. We've got time for one question.

Speaker 4: In your experience when disease progresses after the actinium therapy, is the disease PSMA positive or negative?

Mike Sathekge: The scan? The PSA have actually been going higher on those that have progressed and the scans usually have stayed the same or gotten more lesions. But some of them have had a mixed situation wherein the other side will respond, and then we have a more extensive disease on the other or on one side, which is a bit of a problem that we are still thinking about what could that be? Could it be that the tumor is really rapidly growing than the two months that we are having and therefore we could have benefited if we have perhaps treated six months or even who knows, five months? I mean, five weeks, rather than the eight weeks that we are speaking.

Speaker 4: I mean ultimately, the disease that progresses, is it because it's refractory to a PSMA targeting agent because it doesn't express PSMA?

Mike Sathekge: But you still see some uptake on the scan. So meaning that there is some expression there, so otherwise, if we have seen nothing, I would say, well, so it's a mixture of what is happening, could be rapid growth, it could be a mutation, but there is some expression.

Speaker 2: Thank you very much.

Mike Sathekge: Thanks.