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Phillip Koo: Hi, this is Phillip Koo and welcome again to another lecture in our Society of Nuclear Medicine and Molecular Imaging series on prostate cancer imaging and therapy. Today we're extremely fortunate to have with us Dr. Andrei Iagaru from Stanford University. He's a professor of radiology at Stanford and also chief of nuclear medicine and a world's expert on multiple topics related to prostate cancer, but today he'll be sharing some of the latest information regarding Bombesin, which is an exciting new frontier for prostate cancer imaging. So Dr. Iagaru, thank you very much for your time and your expertise.

Andrei Iagaru: Thank you very much for the very kind and generous introduction. I am honored to be a part of this series and I will thank the Society of Nuclear Medicine and Molecular Imaging for giving me the opportunity to present the following slides. This is part of the series in prostate cancer and I will discuss the gastrin-releasing peptide receptors as targets for prostate cancer theranostics. We are fully aware that prostate cancer continues to remain the main killer in men in 2019. As well as highest incidence expected at about 175,000 patients, second after lung and bronchial cancer as far as a number of deaths each year. So this is a continuous high-issue item for health care systems, not just in the US, worldwide. And of course this is a complex topic, but how we diagnose and how we treat these patients, it's a very important part of the creation.

If you go to any meetings these days that looks at imaging or urology or oncology, PSMA will come up as one of the most prominent areas of clinical research and clinical utilization. And I want to fully acknowledge that my talk today is not meant to try to convince you that PSMA is somehow not good or that we should not use PSMA, the topic that I'm going to present is related in a sense to PSMA in that cancer, it's a very complex biological process and there must be more than one target for what we do in order to offer a lot more to our patients. So think of the GRP-Rs, the gastrin-releasing peptide receptor says, adjuncts to PSMA and perhaps others in the management of patients' prostate cancer. I want to disclose that the following slides will show data from research studies. These three, the pharmaceuticals are not FDA approved and are not available commercially in the United States and if you want to learn more about the trials that are active in the US and worldwide, clinicaltrials.gov is a wonderful resource.

So what are the gastrin-releasing peptide receptors? This class of receptors are a G-protein coupled and overexpressed in many major human cancers. For the purpose of today's topic, I will refer to prostate but more than 80% of estrogen receptor-positive breast cancer also overexpress it, some small cell lung cancers, some ovarian cancers and this is also expressed on the tumoral vessels of urinary tract cancer. So it's a target that also, studied most extensively in prostate cancer, has the potential for diagnostic and therapeutic purposes in other malignancies as well.

I want to briefly touch on the issue of agonist versus antagonist. The agonist tracers require an activated receptor. They then internalize and in theory, treatment with agonists will have a higher rate of success because there will be damaging inside the cell, not from outside. Antagonists have the advantage of not requiring an activated receptor so you can achieve a much higher concentration by binding an antagonist towards receptors than an agonist, so I think that that's something that is very important. As far as a GRP-R agonist, bombesin agonist, the majority of the field moved away from them.

There are currently only three agonists that have been translated clinically and they're listed here. The reason why people moved away from bombesin agonists is the fact that they elicit adverse events once injected. The GRP-Rs are overexpressed also normally throughout the GI tract and in the pancreas, so there are GI symptoms when you give an agonist. However, when you give an antagonist, this is not the issue. In addition, there is more and more evidence that actually the higher concentration of binding when you give an antagonist results in improved lesion detectability and this is a very elegant study where patients with prostate cancer as well as healthy volunteers were imaged both with an agonist and with an antagonist and the authors demonstrated that the antagonists have higher signaling lesions.

So for example here, this an example from this paper. In A, we have a bone scan that it's unremarkable, anterior view, posterior view and then in B, we have the antagonist RM 26 and at the bottom, in C we have a maximum intensity projection image from an agonist, gallium bombesin. And then transaxial PET and fused PET/CT images. And you can appreciate that there are multiple skeletal and nodal lesions that are seen with the antagonist but are not seen with the agonist. So this paper very elegantly shown that as far as GRP-Rs, antagonists are better than agonists.

These are several of the antagonists, the bombesin antagonists, that are used in clinical trials. And I'm going to show you what has been published in a summary over the next few slides. And then, later on, we'll show you our experience at Stanford with one of these. The first experience was published by this group, a collaboration between several centers, between Athens, between Erasmus, and Bad Berka in Germany. They looked at patients with breast and prostate. There were no adverse events and they identified a good number of the lesions. This is an example where this agent was compared. So we have the bombesin antagonist on the left in A and the choline image in B, and you can see that there are lesions, these are a retroperitoneal and pelvic lymph node that are seen perhaps even a little bit better with the bombesin antagonist than with fluorocholine. So these were very encouraging results.

This was then improved and translated into these other radiopharmaceutical, gallium 68 NeoBOMB1, the same group. Again, they tried it in humans and they showed that you can label it with gallium 68, gallium 67, indium 111, lutetium 177, so truly a theranostic there with multiple, I suppose, for diagnostic imaging as well as lutetium 177, for potential translation to therapy. And these are examples demonstrating the distribution of disease on the left in the panel on the left in the prostate gland. So primary lesion in the panel on the right in multiple retroperitoneal pelvic and mediastinal lymph nodes. So again, excellent initial data that is encouraging. And this study, this radiopharmaceutical is currently in studies that are ongoing.

Of course for purposes of commercial distribution would be better to have a fluorine labeled peptide, particularly say, fluorine-18. The molecule is slightly modified, but it's enough to make it not work as well as with the gallium 68 labeled versions. So this is work that was done in Zurich in Switzerland. They also compared these F-18 labeled bombesin antagonists with fluorocholine, and it did not quite work out. So this, as far as I know, has been abandoned. And that means this image here show [inaudible 00:08:15] however much less than what was seen with choline in these patients. Of course, a true theranostic pair will have something that will allow you to do the symmetry prior to the therapy, hence the labeling with copper 64. Copper 64 with a 12 hour half-life would allow someone to do multiple images. So, therefore, being able to calculate the symmetry if the symmetry is needed prior to therapy.

Very elegant work by this group led by Professor Weber. You have a high contrast of tumor to prostate for this radiopharmaceutical, also bombesin antagonist, and they show a nice correlation with histology. So here you can see a very nice signal in this primary prostate cancer on fused PET/CT in panel A than on PET in B and then very nice demonstration of the staining for gastrin-releasing peptide receptors in the histopathology slide.

So what is a normal biodistribution? We at my institution have the largest experience using this gallium 68 RM2, also a bombesin antagonist. So there's nothing above the diaphragm. Minimal if at all distributions throughout the esophagus. Minimal hepatobiliary clearance, which has advantages in that it will not have a lot of optic in the bowel. Masquerading for lymph node, et cetera. It has high optic in the pancreas. That's where these receptors are located.

But the pancreas, it's a radio-resistant organ and also the doses that one would give both for diagnostic as well as for therapeutic purposes will not exceed the maximum allowed dose to the pancreas. The kidneys are the main route of excretion. You see kidneys, you see bladder, there is some optic as well minimally through the bowel. But rectum also has a little bit of optic. As I said, kidneys, ureters and bladder are the highest rate of exclusion for these radiopharmaceuticals.

So the first thing that was done, this was the group in Turku in Finland, they looked at the biodistribution, radiation, the symmetry and they've shown that it's safe to introduce these in humans. These are very fast, one minute per bat images demonstrating the whole-body distribution. And what you see early on is what you see on the delayed 60-minute images. So stable distribution of the radiopharmaceutical.

Then the same group looked at prostate cancer patients and they looked at either primary patients whose biochemical recurrence and they compare this with acetate and fluoromethylcholine and the sensitivity specificity and accuracy of the tracer were pretty high, actually. So these are encouraging results. On the panel A, you see a coronal fuse. That's a key slice of bombesin of gallium RM2 PET, and then lymph nodes marked in panel B as well as in panel C. What is interesting in this work, the authors have shown that the optic in the prostate cancer was higher compared to BPH benign prostate hypertrophy or normal prostate tissue. So these high optic makes it a target that's favorable for diagnosis of prostate cancer, either at initial diagnosis or at biochemical recurrence.

This is a recent work, again led by Professor Weber where they've shown that gallium RM2 PET/CT perform. We've seen a few weeks of multiparametric MRI and prior to prostatectomy had yielded pretty good results. They also demonstrated that on immunohistochemistry analysis that the GRP-R staining is somewhat weaker than for PSMA. However, the two were spatially incongruent, so we are looking at two different biological processes and that's what makes this class of radiopharmaceutical attractive. There was no correlation with the Gleason score and they also demonstrate the optic being much higher in the dominant prostate cancer tumor. Again, higher than in BPH, higher than the normal prostate glands, so confirming the results of the other group and a very nice correlation with the histopathology. You can see marked in ink the extent of the prostate cancer and you can see how intense the optic is in panel B and corresponds to the lesion seen on multiparametric MRI.

This another example demonstrating in this case stronger staining for PSMA at the top. However, the signal was very strong in panel C, a little bit less demonstration of the GRP-R receptors here.

What is our experience? We have several trials that my execution using gallium 68 RM2. The first one that I'm going to share some results is in the initial staging of prostate cancer. To date, we have 28 participants with either intermediate or high risk prostate cancer image prior to prostatectomy. What are the results? We were able to find the disease in all of these patients. In the case on the left, you can see focal optic in the prostate and it correlates very nicely with the image at the bottom where the pathologist has marked in ink the extent of the cancer. What is nice about that the unique use here is that the urologists are doing a 3D mold of the prostate based on the MRI. The prostate is taken out in one piece, sliced and then the images are sent to pack. So in fact afterward you can review in packs, PET/CT, MRI, and histopathology. So a very nice correlation of the imaging findings and pathology findings.

The case on the right. I had the tumor located anteriorly that crossed between the left and the right lobes of the prostate and you can see again marked very nicely on pathology in ink that the primary prostate cancer was crossing between the left and the right lobes of the prostate gland.

The largest experience to date is at biochemical recurrence. This is a study looking at gallium 68 RM2 PET/MRI. In this patient population, we have data analyzed from 84 of them. To date, we enrolled 95 patients. We don't have the followup for the most recent 11 of them. We had very strict inclusion criteria. These patients had to have biochemical recurrence either by AUA or ASTRO criteria, but also negative CT or MRI and negative bone scan prior to enrollment. And despite the fact that conventional imaging was negative, we were able to document the presence of disease in about 70% of the cases where the MRI was positive in about a third of these cases. So 70% positivity rate. It's pretty high and it's comparable with other results that are published with other radiopharmaceuticals.

There were statistically significant differences in PSA values between patients with negative scans with a mean PSA of 1.9 versus those with positive scans with a mean PSA of 9.7. These are some examples in the following slides. You can see here marked with arrows a tiny two to three millimeter pelvic perirectal lymph nodes that we do not have histopathological confirmation that these lymph nodes were then treated with radiation therapy and there was a drop in PSA and these are putative sites of disease in our opinion.

This is a very interesting case with a focal optic demonstrated on the liver capsule. This was biopsied and proven to be metastatic adenocarcinoma of prostate origin and it was the only site of a recurring disease in this patient. You have the followup MRI that was used for biopsy guidance, and as I said, this area marked by the arrow was biopsied and proven to be solitary metastasis of adenocarcinoma of prostate origin.

Let's look at these results here in this table. We're showing four different quartiles, PSA quartiles. 0.2-1, 1-2, 2-5 and 5+. The PSA values in red for a patient with negative scans and in green for patients with positive scan. So our positivity rate for PSA less one, 50%. 1-2, 70%. 2-5, 80%. 5+, 90%. So these numbers are comparable, as I said, with other classes of radiopharmaceuticals, but we do not want to have just another class of radiopharmaceuticals. We want to see if this is actually beneficial for patients.

So let's try and now see are we talking about PSMA versus GRP-R? Frankly, no. We Shouldn't be talking about this class of radiopharmaceutical in these terms. What I think we should discuss is PSMA plus GRP-R because I think that in a significant number of patients, the combination of the two will provide more information than either one used alone.

So let me try to convince you of this. By chemical recurrence, we have 29 patients who had both RM2 and PSMA-11 scans. And while they were positive in about two-thirds of these patients and showing similar lesions or same lesions, there were remaining one-third of the cases where either one or the other was positive and the other negative or the one showed more lesions than the other. So this is a small sample, but it's one that suggests that there is a role for both radiopharmaceuticals.

In this example on the left, we have the RM2 scan demonstrating some lymph nodes in the pelvis. However, not matching the true extent of disease that was seen on PSMA. So multiple nodal metastases in the pelvis and retroperitoneum. The flip side here is this other patient, so bombesin on the left, demonstrates multiple retroperitoneal lymph nodes above the pelvic radiation field at biochemical recurrence. Definitely more than can be seen with PSMA-11. So if you just look at one you would say that one tracer is better than the other. But having seen many such examples, I think that there is a significant role for gastrin-releasing peptide receptors imaging in the future.

What is also important, I think it's what these tracers may tell us about how aggressive the tumor is. So on the left, we have graphed out the PSA velocity in patients with negative scans versus positive scans. So what this tells me is that you can have patients that will be false negatives. We will miss some lesions, but because those seem to have low PSA velocity, maybe it's okay if we miss those patient, maybe those cancers are indolent and we should not treat. While these ones that we find with bombesin, with GRP-R imaging, are the ones that are more aggressive because they have a higher PSA velocity. This did not hold true in our cohort for PSMA-11 where the PSA velocities between negative and positive scans were not statistically significant as far as differences. So small cohort, but interesting and promising preliminary data.

We also wanted to verify how these two compare as far as intensity of optic. And we looked at this for lymph nodes, prostate, seminal vesicles, bone metastasis and all of them bundled together, and there are some differences. It looks like for lymph nodes, seminal vesicle, bone metastasis, the intensity of optic with PSMA-11 is higher, however, these differences were not statistically significant.

And very exciting data. Looking at treatment with Lu-177 RM2. This is from a center in Santiago in Chile. Professor Amaral did this work and with Dr. Kramer there, they treated a few of these patients, so there is now those imagery data. These were patients who are very extensive disease, as you can see here. Multiple osseous metastases. What is interesting is that by 168 hours, which is the set of images on the right, there is a persistent signal in the metastasis, but the optic in the pancreas has washed out quite significantly. So interestingly, the prostate cancer lesion retained the tracer. Normal tissues don't seem to retain it. So I am personally very excited about these findings and I hope to be able to start therapy trials with Lu-177 RM2 at our institution as well.

So to summarize, these, the gastrin-releasing peptide receptor antagonists can be used in various cancers including prostate GRP-R PET imaging shows promising results, both at initial diagnosis as well as at biochemical recurrence. We're seeing that they are likely to have a complementary role to PSMA imaging and therapy, but this entire field of GRP-R diagnostics, it's still in infancy and a lot of work remains to be done. It's very exciting and I hope more and more centers will start using this class and provide data in support of their use.

With that, I want to thank people who contributed to this work. Many of my colleagues, physician residents, and technologists whom I want to acknowledge here. With that, I thank you for your attention.

Phillip Koo: Great. Thank you very much for that. A great talk. Just a couple of questions. So you know, I think one thing that we're all recognizing is the fact that prostate cancer is a very heterogeneous disease. I may agree PSMA is extremely exciting and in terms of diagnosis, diagnostic capabilities and therapy, it'll have a large impact on how we manage our patients. This idea of complementary use of some of these novel radiopharmaceuticals I think is something that we're recognizing will be of more importance moving into the future. Can you talk a little bit about what you are doing or what is occurring around the world with regards to these types of combination radiopharmaceutical trials of that type of nature?

Andrei Iagaru: So at my institution, we have a few small pilot studies. Some of them are at the initial diagnosis some of them are at recurrence. There are some also to evaluate response to local treatment. There will be a study beginning to enroll patients before high dose rate brachytherapy. So HDR brachytherapy. The issue there is that if you just use MRI or even PSMA-11 alone, you may miss a lesion in the contralateral lobe of the prostate. And if you only treat one side, then no wonder there will be disease progression later on. So we will have this combination of PSMA and GRP-R imaging before and after HDR brachytherapy to see if we can predict response and also if we provide additional information to what multiparametric MRI is providing in that scenario.

I think that another very interesting area of research is that oligometastatic disease, that's when you have a chance of potential cure. So combining therapies in that scenario is something that we are very interested in pursuing. There are other groups throughout the world, working on this in France, in Italy, in the Netherlands. So I think that you will soon start seeing more data.

Phillip Koo: Great. So another question I had was how does this perform with regards to treatment response? Because this seems like an area where we really don't have much guidance in the literature with regards to how we monitor patients undergoing therapy. Any thoughts on how GRP-R might perform in this setting?

Andrei Iagaru: I only have anecdotal data. A few of these patients that received external radiation and then we re-imaged them and the signal was no longer present and that correlated with the clinical status and the PSA drop in response to external radiation. I agree with what you said. It's an area where we need more tools and perhaps this will be one of them. But it's anecdotal data and not something that was done in a prospective way or under a research plan.

Phillip Koo: Great. So the final question is, since we have someone of your expertise on the line, just taking a higher level overview of what prostate cancer imaging and therapies will look like in the next, let's say three years, where do you see us in three years, and what advice do you have for the urologist and GU medical oncologists who are members of the ureteric community?

Andrei Iagaru: So I'm confident that in next year there will be new imaging, a PSMA agent for imaging approved in the United States. So that will probably result in a 20, 30% gross in the PET volumes at most institutions. The treating physicians are prime for this. I went to AUA this year and there were multiple presentations on PSMA imaging. This will probably be followed soon after by a lutetium PSMA approval. And I think that you know, the concept of multidisciplinary care that we learned to apply in neuroendocrine tumors with Lutathera and gallium dotatate to have to be transitioned into prostate cancer imaging and treatment. I think that most institutions who have excellent collaborations between urology, medical oncology, radiation oncology, and radiology and nuclear medicine, and in my view, that is the only way to make this a successful field.

Beyond three, four years, there will be other classes I think of radiopharmaceuticals. Hopefully one of them being bombesin imaging and therapy and they will, they will provide a more complete armamentarium for the treating physicians. I think that for the nuclear medicine community, we need to continue to outreach to our colleagues in urology, medical oncology, radiation therapy, published in their specialty journals, go to their meetings and show the value of what we do for their patients. And that will be the foundation of a solid and successful partnership.

Phillip Koo: Great. Well, thank you very, very much for sharing your time with us and your knowledge and we really appreciate this and we really look forward to seeing more of the great work from you and then your group at Stanford.

Andrei Iagaru: Thank you. My pleasure.