Case-based Approaches: PSMA and Personalized Prostate Cancer Care - Frankis Almaguel
August 13, 2019
Frankis Almaguel, MD, Ph.D., Director, Molecular Imaging and Therapeutics, Loma Linda University Cancer Center, Center for Health Disparities and Molecular Medicine
Phillip J. Koo, MD, Division Chief of Diagnostic Imaging at the Banner MD Anderson Cancer Center in Arizona.
Phillip Koo: Hello, this is Phillip Koo from UroToday. We're very fortunate to have with us today, Dr. Frankis Almaguel, who's Assistant Professor and Director of Molecular Imaging and Therapeutics at the Loma Linda University Cancer Center. Thank you very much, Dr. Almaguel, for joining us.
Frankis Almaguel: Thank you for the invitation. The goal of this second presentation is to talk to you about what I believe is the most exciting aspect of PSMA because therapeutic interventions based on PSMA have the potential of changing a lot of ways, the treatment of prostate cancer and how personalized care is going to help these prostate cancer patients.
Let me go again and show you the molecular of PSMA, how this marker is able to show us where a cancer cell is in the midst of normal tissue. It's very important if we're going to deliver therapeutic payloads to only those cancer cells. This is also key for specializing medicine. Again, we were able to select the patients that have this biomarker and now that we have this population of patients with the expression of the biomarkers, now we can see where we were not able to see well before. The anatomic imaging is great but now, having that insight to the cellular, to the molecular level of information will basically tell us where the cancer cell is so that we can actually now turn that into a therapy. Finding that wolf that is hiding within the sheep.
Again, theranostic principle. We have a radioisotope that will give us the opportunity of seeing, visualizing where the cancer cell is and then we can switch this radioisotope for an isotope that will destroy the cell, will damage the DNA of those cancer cells, without damaging the surrounding, with minimal damage to surrounding cells.
How did this start? Basically, it started by a group of physicians really thinking about how can they help patients who cannot be helped in any other way. The Helsinki declaration was modified and this was added. Just acknowledging that we will do the best we can for this patient, even though these unproven interventions that were available. Basically, no treatment with PSMA was done without really thinking to the wellbeing of these patients.
The first study that was performed, 119 patients with metastatic castration-resistant prostate cancer patients, basically were identified and these patients had bone metastases, lymph node metastases, visceral metastases. You can see in the diagnostic imaging with PSMA. After the treatment, 76% of these patients have a reduction in PSA. Many of these patients underwent significant degrees in the amount of the disease, very encouraging.
They have the breakdown of the response, basically, they had significant success with these patients. But more important than those patients with remission, patients with partial remission and patients that achieved disease control, which is basically the majority of patients, with almost 70%. The important is that the toxicity was very low. No evidence of renal toxicity. As you know, you could see the kidneys clearing out PSMA in the scans but no evidence of renal toxicity was detected in the study. No grade three or four histologic toxicity was seen. A mild dryness of the mouth and in this case, most of them were reversible. No diarrhea, even with significant intestinal uptake, so therapies that are effective with low toxicity.
Their summary for this specific trial, these patients have a significant symptom improvement. The therapy were effective and of course, it has the potential to benefit a lot of these patients. Of course, we need more trials and we will discuss a little bit more. This trial from the group of Doctor Baum in Germany, 56 patients with progressive metastatic castration-resistant prostate cancer, basically the trial is telling us these patients, 80% of them responded by decreasing PSA. Increased the survival and if you can see, again, the repeating trend is very low adverse effect. No evidence of nephrotoxicity, no significant change in platelet. These interventions have less side effects than the current available therapies for prostate cancer in the market right now.
This is one of the pictures that I was shown from this study. You see this patient with full metastases and after three cycles, has a very significant decrease in the amount of disease. Actually, I think very interesting for this patient, has very low PSA with all this metastases. That will be a topic for another talk, but what I'm trying to say is that this therapy has a potential to revolutionize the way we treat prostate cancer.
Based on these studies in Bad Berka, if you can see the current therapies available for prostate cancer, it's giving you a maximum 4.8 months, medium progression-free survival. PSMA has a significant increase in medium progression-free survival. Definitely we need to look more into these studies and you'll see in future slides how this is happening.
This is very interesting. They describe two distinct patterns, the diffuse pattern and the spot pattern. This diffuse pattern has such a burden of disease that experts in the field are saying that maybe we should try alpha-emitters because of the specific characteristics. The first in-human treatment with alpha-radionuclide for PSMA was performed in two patients. Basically, it's a study of two patients, showing almost complete response. Of course, everything starts with validating that these patients have PSMA expression and then after the therapies, you can see how the PSA has been dropping from almost 3000 to 0.1. This study from Clemens Kratochwil in Germany showing us that a new radioisotope with a little bit more power than lutetium is also able to help patients with prostate cancer.
They basically summarize saying that these targeted therapies with PSMA, although experimental, have significant potential. If you can see this picture here, you have patients that were not responding to lutetium therapy. When they were switched to actinium, they started responding again. There is a lot more that will come from this.
There was another bigger trial with 40 patients. This is basically end-state metastatic castration-resistant prostate cancer. Again, the short tissue penetration of actinium 225, they decided to repeat this and in this patient with the diffused pattern of disease. Again, 31 out of 40 patients treating with this protocol, 87% of them have a PSA response, I mean decreased PSA. Even though this was the last line of therapy, they give this patient nine months in average. A few of them have enduring responses for more than two years.
Safety. In this case, using actinium, they had a little bit of issues with toxicity to salivary glands. Basically, all patients had grade one, grade two. Patients in this case, they tried to tell you that this patient had extensive bone marrow metastasis and background anemia, grade three anemia. A patient with only patient kidney, with a grade three renal failure prior to the therapy developed grade four toxicity. They're still safe therapies but has some things that we have to address.
They did this study showing that if you're able to inject the salivary glands with botulinum toxin, you decrease the uptake of PSMA and this can tell us that there might be something we could do for eliminating or decreasing the toxicity to the salivary glands. That's a topic for another study, but the summary for that study was that this therapy had high anti-tumor activity and clinical efficacy against the tumor, and maybe a little bit higher than lutetium. Of course, the radiation to the salivary glands is an area of concern.
This study that I'm going to talk to you about is pretty interesting because this study was performed in South Africa with patients that chemotherapy was not available to them, so they were enrolled in this trial for chemotherapy-naïve patients. 17 patients were enrolled and they were treated with actinium 225 PSMA, starting with this specific megabecquerel decreasing. The important thing is that 17 patients treated with advanced prostate cancer, treated with actinium 225 in two month intervals.
Why was this trial unique? Because they were able to get to these prostate cancer patients earlier, without undergoing chemotherapy. In three patients the treatment was discontinued after two cycles, due to very good response. Six out of the 17 patients received additional treatment after the third treatment, and the PSA was measured every four weeks. These are the results for this trial, basically, 82% of the patients had PSA decline. More than 90% was seen after the treatment. 88% of the patients had 50% decline in the lesion avidity for when we were imaging with PSMA. Where we are standing, 65% of these patients got complete resolution. If you see in the picture, the prior trials with patients that were end-stage and patients that had very advanced prostate cancer, and not only advanced but many therapies were performed before, had actually significantly less in terms of success, these patients in this trail with chemotherapy naïve patients had a significant increase in response. That's something that we might have to look more in the future.
Another picture, this patient very diffuse disease. After these four therapies, you see the decrease in PSA and the decrease in the amount of disease. They concluded saying that, very strong words, remission could be achieved and remarkable therapeutic efficiency, very low toxicity, basically they claimed no acute toxicity of the treatment agent. How can we evaluate this?
It goes back to of course with having a targeted therapy that is affecting less, minimizing the damage to the adjacent cells. I believe that we are here, getting to an area where the future is now. We have many questions but we know that these therapies have the potential of being with us for a long time now. Since the future is here, how are you doing to deal with the amount of patients? Remember we said about three million patients with prostate cancer are living in the US alone. These therapies might be able to help these patients. In the future a lot more providers with be desiring that their patients might get these molecular imaging techniques so they can decide what to do with these patients.
Artificial intelligence is here to help us. They're being developed right now and they will help us manage this flood of information and will help us monitor and will help us achieve our goals. We're going to have to go through a lot of these cases and definitely we will receive this help. Basically, the nuclear radiologists will be able to see this scan and the program with help identify these lesions. Where these lesions are and it basically has the potential of assisting us with very important decisions. If we have to spend half an hour in each scan, detecting, looking for all these small lesions, it will be a big task. If we can get a bit of help it will be very well appreciated.
Basically, I'm trying to say that the results for PSMA therapy are very promising. Future trials are needed and we will be hearing about this technology in the near future. The VISION trial in America and Europe is already going and in Australia, we have the TheraP trial, so soon we'll have more information on how this therapy, this molecular imaging intervention is going to be helping the patients. I think we just need to stay tuned, and thank you again for the invitation. I'm very passionate about this field and about how nuclear medicine will help these patients. It's just an honor to be part of it.
Phillip Koo: Great. Thank you Dr. Almaguel. Just a couple of followup questions. In your opinion, from the imaging standpoint, what role do you think bone scans and CT will have in the future now that we have these next-generation imaging tools, such as PSMA-PET?
Frankis Almaguel: Well, right now if you ask me, you see some of the data that I presented, we can see a lot more information with PSMA imaging. I believe that when everybody is caught up with the technology and this information has gotten to the patients and to the referral physicians, basically, they will do a lot more PSMA than CT and bone scans for these specific conditions.
Phillip Koo: Right, so then on the therapy side, what are your thoughts, you presented some data, some trials, there were some patients where 30% of patients didn't respond to lutetium-177. In the other trials maybe single digit, 8%, 5% of patients didn't respond, what are your thoughts as to why some of these patients did not respond? Because there were pre-therapy imaging that confirmed there was expression of PSMA.
Frankis Almaguel: Actually, I was trying to go into comparing the last trial that I showed you, patients that were chemotherapy naïve. You see these patients responded much better than the others. At this point we don't know, that's why we have these big trials going, but I can tell you that in the basic science community we know that they are insights into how chemotherapy is promoting the production of stem cells that might not be as responsive and basically been resistant for these therapies. At this point we don't know, but yes we have expression of PSMA. All patients that were treated had PSMA expression and you see the patients when they were treated at end-stage with all these other therapies in between, I mean before the PSMA therapy had less response than patients that were chemotherapy naïve.
I think that we have to see what will happen with this technology applied to patients earlier in the disease process, but like I said, there are still a lot of questions that need to be answered and I can tell you that we are in a good position to help these patients. We just need to find those answers and to document the safety and basically, share this with our preferred physicians. Neurologists and people that are really caring for these prostate cancer patients. They need to help us understand and together come up to a decision how we can add this to the tools that we use to help these patients.
I think that is going to take a multidisciplinary approach and many people involved to basically, get to the right flow state. This is team science, this we cannot do alone. We need the help of others and this basically has a good potential but at the same time we have to make sure that we're not missing something. I'm just excited because when they presented evidence in the past, patients with this distant disease were very hard to help and now it's presenting something that has the potential to help those un-helpable patients in the past, so very excited. But at the same time, like you said, we don't have all the answers.
Phillip Koo: Great, thank you, Dr. Almaguel, for sharing your knowledge with us today, and thank you for your time.
Frankis Almaguel: Thank you.