PSMA Theranostics in Prostate Cancer SNMMI - Richard Baum
December 14, 2020
Richard P. Baum, MD, Ph.D., Department of Molecular Imaging, Theronistics Center for Molecular Radiotherapy and Molecular Imaging, Zentralklinik Bad Berka
Richard Baum: Good afternoon everyone. Before I start, I would like to ask, is there someone from Sweden in the room? Nobody, thank God. Because Germany just won against 2-1 in the 97th minute, 97th minute against Sweden. Okay. I have no conflicts of interest concerning this lecture.
In our center, in Bad Berka, we are seeing about 800 prostate cancer patients every year, not only for treatment but also for diagnosis and restaging. So we do not have a urology or a uro-oncology department in our center. It just shows how this new diagnosis and therapy is really attracting prostate cancer patients. We are doing around 400 PSMA mediated radioligand therapies.
In the first year, we are surpassing now neuroendocrine tumors. And we are building up... Well, we have built up a Theranostics Research Center, which consists of molecular imagine. Of course, our molecular therapy including dosimetry, medical physics, and so on. And although we have a very good molecular pathology, preclinical imaging we are doing mainly in collaboration in this center.
So how do theranostics work? For those who are not so familiar with the concept, it's actually working according to the key-lock principle. Now, the target or the lock on the tumor cell are antigens, or GPCR, like somatostatin receptors, or enzymes like PSMA, or transporters. And then, we have some molecular address actually, which fits into this target like a key in a lock. And in the case of PSMA, we are using small molecules. But in the path, there were also antibodies used.
Then we have a linker and a chelator, which is like a cage and holds our diagnostic agent, labeled to the PSMA, like gallium, fluorine, but also our cytotoxic units like lutetium or actinium. Concerning radio peptide therapy in neuroendocrine tumors, we have done over the last 20 years 5700 treatments in more than 1500 patients, mostly now with lutetium but also starting now with the alpha emitters.
I show this slide because it's exactly 20 years ago when we treated the first patient in Bad Berka with radio peptide receptor radionuclide therapy. And it took quite a long time until this landmark publication in the New England Journal on the Phase 3 Trial of Lu-Dotatate, which recently has been approved in the United States. So what will be the future of cancer treatment? I'm convinced that precision oncology will be the way to go. That means that cancers will be classified by molecular phenotypes. And the organ site will be more a secondary classification. That means that we will not speak anymore about lung cancer, colon cancer, breast cancer, prostate cancer. But we will speak about HER2 expressing cancers, somatostatin expressing cancers, PSMA expressing cancers.
And these molecular phenotypes can be quite accurately determined by PET/CT, or by SPECT/CT, or other measures, but mainly establishes actually PET/CT using cancer type-specific probes. And the treatment will be targeted specifically against the tumor of the patient, which is what we call "precision oncology". And I really think that nuclear medicine, as a specialty, should be proud that we are really the first ones who are using precision oncology in daily practice, and not only in theory or in preclinical studies.
Now, prostate cancer is a paradigm for this approach, as molecular radiotherapy is applied based on the molecular phenotype, mainly PSMA expression of the metastases as defined by PSMA PET/CT before starting the treatment.
So, you heard already about the epidemiology of prostate cancer. One out of six men will be diagnosed. One out of 12 will be suffering. And one out of 25 men will die of the disease. And in the European Union, for example, every 15 minutes, a man is dying of hormone-refractory prostate cancer. You have seen the slide. And Doctor Charvat [inaudible] just mentioning that over the last years there have been a lot of new agents introduced. And if you look at the results of these prospective studies published in the Journal of Clinical Oncology, one finds the survival benefit with chemotherapy, which is around nine to 10 weeks, not months.
For the second generation, deprivation therapy is three to five months. And progression-free survival ranged from 16.5 to 18 months, and overall survival, in early stages of the disease, from 14 to 32 months. Please remember these numbers, because I will come back to them at the end of my talk. So there's an urgent need for more effective therapies.
For example, docetaxel is a standard first-line chemotherapy in patients with metastatic castration-resistant prostate cancer. However, the median overall survival of these patients is just more than a year. And there are a lot of adverse effects, especially concerning hematological side effects like neutropenia in 84% to 99% of the patients, but also polyneuropathy, peripheral nerve damage, and so on and so on. The same is true for cabazitaxel, which is mainly used after docetaxel chemotherapy. And again, the overall benefit in survival is just 2.4 months, when compared to mitoxantrone.
And cabazitaxel has a very high rate of anemia. Nearly all patients, in 98%, have anemia, some very severe Grades 3/4 anemia, and also neuromuscular, skeletal, renal, respiratory, adverse effects. So the shortcomings of all of these new therapies are that some are available only in the United States or in Europe. It's not really clear if PSMA is a useful marker in these castrate-resistant prostate cancer patients. The therapy sequence is not clear at all, so when to use which agent, at what time to start with this agent. And toxicity, I have discussed already. But I should also mention that there is financial toxicity, especially of these newer agents, because some are very expensive costing over $200,000. So like a Rolls-Royce, everybody wants to have it, but nobody can afford it.
And if we look at Germany, for example, Xtandi® and Zytiga®, the cost is around $70,000 or $77,000 per year. So these drugs are not cheap at all. PSMA, on the other side, is a cell surface enzyme that's continually internalized. It has glutamate carboxypeptidase two activities. So this should be the correct name for PSMA, because it's not prostate cancer-specific. It's expressed in breast cancer, in many other cancers like renal cell cancers, in neovasculature, for example, in glioblastoma and so on. So it's a simple name, PSMA. But it's not a really correct name.
And PSMA expressed, especially in higher-grade tumors, metastatic disease, and hormone-refractory prostate cancer. So Henry Wagner once said FDG is the molecule of the century. And I believe that PSMA is really the target of this decade. As you can see from this table, in nearly 1000 patients, they found PSMA expression, especially in the higher grade tumors like shown here in Gleason four and Gleason five tumors, of nearly 100%. And what is also important is that benign prostate hyperplasia, BPH, is negative for PSMA.
Now a breakthrough was the labeling of this urea-based compound with chelator HBED-CC by the Heidelberg group, by my good old friend Eisenhut. And this was a breakthrough because the images were very convincing, very little background, very crisp images, and very nice localization. And I will show you one example of a prostate cancer patient Gleason = 9 (4 + 5), who had prostatectomy with lymph node clearance one month ago. And histology reported one situation. So there was a microscopic residual disease. And the postoperative PSA level was 0.37. So if you ask a urologist, "What would be your decision in this case?" I think 99% would say, "We will eradiate the prostate bed."
But this urologist had some cases we had together. So he sent the patient for a PSMA PET/CT, and asked the question, "Is there legions outside the prostate region before external beam radiation therapy?" And yes, you can see here, there's not only one, there are many lesions outside the prostate bed. Overall, we counted 14 lesions. And if you look at the size of the metastases, they are quite small, three millimeters you can easily detect on a PET/CT. Nine-millimeter lymph nodes still in the upper normal range of CT size are clearly seen. And what was really surprising were these bone metastases despite a PSA level of just 0.37 nanograms per milliliter. And there wasn't only one. There were rib metastases here in the pelvic region.
And you really have to be clear that in these advanced and differentiated prostate cancer patients, low PSA does not mean a low tumor burden. Many urologists are thinking, "Oh, this guy has just a PSA level of 1 nanogram per milliliter, can't be a lot of disease." But this is completely wrong. It's more undifferentiated the cancer gets as less PSA actually is produced. Another advantage of this gallium PSMA imaging is that it is really a one-stop-shop. So you can detect primary tumors. You can detect lymph node bone metastases, and lesions actually in any organ, your image within an imaging time of around 20 minutes. And we have the first specific tracer for localizing bone marrow metastases. And I think this is especially important if it comes to patients with a normal bone scan. Because, as you can see, the cortical is here, it's completely intact. There is no lesion actually in the cortical bone. But there are many lesions here in the bone marrow, which are clearly seen on the PSMA PET/CT imaging.
Now the German Nuclear Medicine Society has to be congratulated for the action of making consensus guidelines for the treatment of metastatic castration-resistant prostate cancers, though the initial indications were a distant metastases with high PSMA expression, confirmed on pre-therapy gallium PSMA PET/CT and progressive disease despite extensive previous treatments. And the recommendation originally was three cycles with six gigabecquerel every eight weeks, and follow up with PET/CT for looking at therapy response.
The data are published in the Journal of Nuclear Medicine, already some time ago. And what I would like to stress here is that there was not only a reduction of PSA levels and legions but also a quite improvement... significant improvement of pain and of the quality of life. And these are... You need not to read this. There are so many publications with lutetium PSMA since 2015, especially from Europe, but also from Australia and other countries. Concerning the dosimetry, we spent a lot of effort in looking at a comparison between different PSMA compounds. And we found the highest dose to normal organs for the salivary glands and the lacrimal glands, and the kidneys which are in the same range like the Lutathera® treatment. But the most favorable dosimetry was found for red marrow.
And this just shows you a patient after half an hour, three hours, 20 hours, up to 19 days, which shows you that this agent is really staying in the tumor forever. Lutetium has a half-life, as you know, of 6.7 days. And if your image, after with a high dose, even after four weeks, you just see the tumor. It clears from all normal tissue and stays with a physical half-life in the tumor. This is one patient I would like to present to you, Gleason 9 mCRPC treated with 9.2 gigabecquerels of lutetium PSMA-617. And you see that he had very high uptake in the bone metastases, but also in lymph node metastases. And the images... Already, after three hours, you see very good targeting of this lesion, especially of one lesion here in the [inaudible] region.
We can do wonderful SPECT/CT images under therapy because of the gamma compound of the lutetium-177. And we are using these SPECT images for segmentation. So we are doing what we call hybrid dosimetry using SPECT and planar images, calculating doses for whole-body normal organs, as you can see here, and also for target lesions. For example, in this patient, you can see that there was a dose of unbelievable 467 Gray to these rib metastases here. But all of the [inaudible], which was prominent, received a dose of more than 290 Gray. So we can really achieve very high doses. Whereas, if you look at the normal body, at the whole-body, there is very little uptake and no significant exposure.
This is a comparison between the median of 132 patients for bone metastases and this specific patient. And you see how different the targeting is. And from that, we can expect of course a very good effect in this patient. Now, the first paper actually appeared in June 2016 from our group. And I think we were the first in the world starting lutetium-177 PRLT in April 2013. And we had quite promising results, for example, this patient with lymph node metastases, and after treatment, there was a complete remission. And the median progression for survival with this agent I and T we were using, from [inaudible] in Munich, was 13.7 months. And the median overall survival was not reached.
This is another quite impressive patient with a lot of disease in the bone, but also in lymph nodes. And again, look at the PSA level, which was 0.05, so nearly normal. And the urologist could not believe our scan. He said he must have different cancer, maybe lung cancer or so. But it was, of course, clearly cancer and metastases from his prostate cancer. These are the lutetium scans under therapy first, second, and third cycle. And you can already see that there is a very good response to the treatment, which is confirmed on the gallium scan. Three months after the treatment with complete remission of the disease. Again, low PSA does not mean a low tumor burden. For these patients, especially if PSA is zero or just around one or two, you have to use other methods to determine therapy response. And the best method we've found is really PSMA PET itself. So it can be used as a theragnostic for electing patients, but also for follow-up and treatment response evaluation of these patients.
So our concept is that we restage this patient. If they are stable and have an objective response, we just follow them by laboratory parameters, including serum PSA. If there is a progression of the disease, we retreat these patients with one or two cycles. So this is a completely different concept of what you are using with chemotherapy. Everyone gets six cycles of treatment and then finished. We have a therapy which can accompany the patient life-long and can be repeated up to 11 cycles we have given now, as you can see from these statistics, until mid-March 2018, we have treated 254 patients with 762 cycles and a mean administered activity of 6.23 gigabecquerels. Most of the patients received three, four cycles, but as I mentioned, even up to 11 treatment cycles.
Now, these patients were really ill patients with progressive disease in all cases, a mean Gleason score of eight, high-risk group. Nearly all patients had received androgen deprivation therapy, ADT. Most have been operated. But also a lot were treated by external beam radiotherapy, chemotherapy, and other agents. These are the sites of metastases. And bone was the most frequently involved site. But there were also a good number of patients having lymph node and bone metastases. We found although 32 patients with lung and 31 with liver metastases, but other very rare sites of disease, like the testicles or the adrenal gland.
This is an example of a patient with hormone-refractory disease. After surgery, external beam radiation therapy, and ADT, he developed lymph node metastases in the para-aortic and para-cava region, as you can see here. And the oncologist recommended to continue with ADT and to additionally irradiate this lymph node metastases by an external beam. And that was done. This is November 2015. One year later, the patient came again with widespread metastases all over, especially in the bone. And the PSA rose to 45. We performed two treatment cycles with lutetium. And fortunately, the patient had a complete remission with a PSA of 0.0, and no sign of disease on the PET scan and on the CT scan.
These are his lutetium scans after 20 and 70 hours, during the first cycle. And these are the scans, at the same time, during the second cycle. And you can already see that there is an excellent therapy response of the disseminated skeletal metastases after a single treatment. So I ask myself if this is really only radiation which causes these really amazing responses. And we have now data which show that we actually stimulate the immune system by our radioligand therapies, that we create new antigens which might play a very important part in this therapy response.
What about the safety of the drugs? These are data with INT, but mostly with a 617 compound. And you see that there is... Even after five years of treatment, we have not seen any Grade 4 toxicity. And actually, the mean serum creatinine and the max three which measures the tubular extraction rate were stable over time in all of the patients. We had even 17 patients with a single functioning kidney. And I would like to show you the data of these patients, using creatinine at baseline, and after each therapy remained stable. So even if you give very high doses, radiation doses, to the single kidney, there is no change. And this is also true for the TR. So lutetium is actually not nephrotoxic at all.
This is an example of a patient with a right kidney. The left was lost after a blockage by these lymph node metastases. You see a very nice response after the treatment cycle. And this is another patient, again, with loss of kidney through ureter blockage by tumor masses. And you see that after treatment the extinction curves look even better for this single kidney. What about hematological adverse effects? We looked at red blood cells. And if you compare the numbers, you see there is no toxicity to red blood cells. The same is true for the white blood cells, and most importantly for the platelets. If you look at the patients with G2 and G3 and G4, even before treatment, there were seven patients. And after treatments, the situation even improved. So we have patients with platelets as low as 20, and we treat. And they increase to 40. So there is no platelet toxicity.
What are predisposing risk factors for higher grade toxicity? Of course, extensive prior chemotherapy, especially with cabazitaxel. Radium-223, we had seen patients with long term drop of platelets after radium therapy. And if you treat these patients, of course, the reserve in the bone marrow is relatively low in those patients I mentioned with extensive bone and bone marrow metastases. We have not seen any organ toxicity, including the liver and other organs which were checked regularly by laboratory tests.
These are again the data for survival benefit from currently recommended treatments and approved drugs. And you see that, including radium-223, all are less than five months. And these are our data. Now in... After five years, 61 months, in 254 patients, we found a median radiographic progression-free survival determined on the CT component of the PET CT of 9.8 months, and an overall survival of more than 30 months. This is really amazing. Of course, not all these patients were last-line. We also had some earlier patients. But this is as compared to chemotherapy and all other agents available, really a very amazing result. And if you look a little bit more in detail, the use of abiraterone or enzalutamide actually is useful because we have much longer survival, more than double as in patients without this newer ADT. So you should continue that.
This is one example. After three cycles of lutetium PRLT, the patient had a 13-month progression-free survival, and then progressed, as you can see again. And we treated him in combination with enzalutamide, which upregulates actually the PSMA in the tumor. And he had again a response to the treatment. What about chemotherapy? Of course, this is a biased analysis because those patients, having already had chemotherapy, came in a worse state to treatment. But the difference for me was really somewhat shocking, that those patients with chemotherapy just had 19 months. And without previous chemotherapy, we achieved 38 months of median overall survival.
So that, of course, led you to ask the question, "What is the best place of PRLT?" And probably, we can do it earlier, like in this 62-year-old internal medicine specialist with undifferentiated prostate cancer, who had progressive disease but he refused chemotherapy because his wife, unfortunately, died of breast cancer. And he had seen a lot of adverse effects, so he definitely said, "I do not want to have chemotherapy." So we treated him with three cycles of PRLT. And fortunately enough, he had a complete remission of the disease, with PSA not anymore measurable. Now you can ask... So he could restart his practice, which was very important for him also psychologically. And he's regularly playing tennis. And you can ask, of course, "How long is his lasting?" This was October 2016. Then, about eight months later, in July 2017, he was still in complete remission. And he will come next week for a restaging, and his PSA is still 0.0.
So taking PSA, which as I said is not a perfect parameter in these undifferentiated tumors, but we observed a decline in 70% of the patients. And for the oncologists, they always ask, "In how many patients, you have degrees more than half?" And that was the case in 54% of the patients.
As I said, one can discuss now if we should use PRLT earlier. And at this meeting, my coworker, Doctor Kulkarni, will present data on the novel or early radioligand therapy in patients with hormone-sensitive metastatic prostate cancer. All these patients had treatment of the primary tumor except for two. And you see that the progression-free survival in this group, at three years, was 91% overall survival, and median progression-free survival of 30.9 months. And all patients demonstrated a decline in PSA level.
So, our conclusion from this data is that the first-line of recurrent prostate cancer is feasible, is safe. We have seen absolutely no adverse effects. And it's also effective. And early introduction in combination with androgen deprivation therapy might provide an additional benefit. But the data, of course, are too small to make a final conclusion. But just to show you one patient who came from Taiwan, and he refused treatment of the primary tumor by an operation. He had big lymph node metastases in the iliacal region, and also a lot of lymph node metastases in the retroperitoneal nodes. And we treated him with two cycles of PRLT. And he showed a very nice response and successive decrease of the lymph node metastases in the primary tumor.
I would like to finish with targeted alpha radiation therapy. You have already heard by Hussein about the advantage of alpha emitters, which have a much higher linear energy transfer and distraction power to the DNA. And we originally started with bismuth-213, which can be obtained from an actinium generator, but has just a half-life of 45 minutes. So you have to inject several times a day. And there were very good data from Mike Sathekge, from South Africa, who showed that it can eradicate lymph node metastases.
So we did a treatment in 10 patients. And to make a long story short, we have seen some effect of this treatment, but not really the breakthrough effects. So one can use it, but it's also not very cheap. The generator costs a lot of money. And logistically, it's quite different to inject the patient several times a day with such a short half-life. And therefore, our conclusion was that actinium-225 should be considered the first choice isotope for alpha therapy of mCRPC, as published by Kratochwil. And I think everyone has seen meanwhile these really amazing results from the German Cancer Research Center.
This is a patient having a response. Even after the failure of lutetium therapy, he was progressive under two cycles of lutetium but showed complete remission of the disease with the actinium. So probably curing the incurable, that's of course questionable. But if you look at these so-called swimmer plots which show actually the duration of two more control compared to the different agents, you see that the relative duration, especially of the alpha therapy, is really convincing. And also, again from South Africa, there were data. In first-line treatment of this patient with bulky lymph node metastases, and it's not photoshopped, it's really a complete remission of the disease.
So severe xerostomia became the dose-limiting toxicity if treatment exceeded 100 kilo becquerels per kilogram, bodyweight per cycle. And we were thinking of how to decrease the salivary gland toxicity. And we were using actually botulinum toxin A, or Botox, injection into the salivary gland. And you see here dynamic salivary gland scintigraphy at baseline and after Botox treatment, with very much reduced metabolism of the gland, which can be also seen here very nicely in the sagittal volume rendered images on the PET/CT, with 64% reduction. And for those who are interested in this topic, I strongly recommend to visit the presentation by my coworker, Doctor Langbein. On Tuesday, he will discuss in detail the results of meanwhile five different compounds we have studied for protection of salivary gland.
I would like to finish with a new idea. Actually, it was my idea to use a combination of lutetium and actinium just to prevent salivary gland toxicity. We used half of the dose. But what we have seen was, for me, the most amazing result I had seen in 25 years of oncology. This is a patient progressive under lutetium therapy, progressive with PSA. In just one single application of 4.5 gigabecquerels lutetium, and five megabecquerels of actinium led to a complete remission of the disease. This is the second patient which really nearly is the same result. And we are gathering the data now and analyzing it. But it seems that tandem PRLT can reduce not only toxicity but might be even more successful or powerful than actinium alone.
Now, these results are fortunately discussed now not only within the nuclear medicine community, but also by the oncologists, and hopefully also funded in future. And I would like to give you these take-home messages. PSMA based radioligand therapy of metastatic prostate cancer is effective. Even in end-stage disease, we see the regression of tumor burden. And we can even achieve complete remission in some patients as last-line therapy. We have... And I did not really go into detail with this, but we have seen really amazing improvement of clinical symptoms. Some patients who are coming for the first therapy are wheelchair-bound. And for the third therapy, they were driving their own car without any problems. So we see also a significant improvement of pain and of the performance stages of these patients.
And I think it will prolong progression-free survival. That is already proven. But very likely, we will also gain a substantial survival benefit for these patients after even exhausting all conventional therapy regimens. It is excellently tolerated in nearly all patients. Many patients ask me if they have been treated by water because they do not feel anything. We have seen no or minimal hematotoxicity in chemotherapy-naïve patients. And there is absolutely no nephrotoxicity, even with quite high activities up to 12 gigabecquerels we have given for a single cycle. In three percent, we see persistent salivary gland toxicity, which is not so high as originally thought.
And for me, as a concept, it's very important that we can select the right patient and predict therapy response by the theranostics concept using PSMA imaging. In the future, I think we have to look into more detail into the tandem alpha radiation therapy, TANDEM ART. We will have new diagnostic probes like, for example, the radio hybrid PSMA labeled with F-18 or with Gallium-68. We will have a lot of new therapeutic radioisotopes probably, or the [inaudible] which we are trying in the near future, in combination with other treatments. And most urgently, especially for approval and for all of you that you can use this therapy, are prospective clinical trials. And the have already started in Australia with this therapy study which is a randomized study of lutetium PSMA versus cabazitaxel. And I'm sure who will win this race. And I hope that this study, which is well recruiting, will soon be published.
I would like to invite you to the fifth Theranostics World Congress in 2019, beginning of March, at the wonderful island of Jeju, Korea, which seems to be now a little bit safer than just a few weeks ago. We started the first World Congress in Germany. We had the second in Chandigarh in India, the third here in Baltimore, and the fourth about two years ago in Melbourne. And you will hear a lot of new compounds going into this theranostic war against cancer. Thank you very much for your attention.