Phillip Koo: Hi, I'm Phillip Koo. I'm a nuclear radiologist for Banner MD Anderson in Phoenix, Arizona. Welcome to our special program titled "A Step Towards Personalized Medicine: PET-PSMA Imaging in Prostate Cancer". We're very fortunate to have with us today, Dr. Andrei Iagaru, who's the Chief of Nuclear Medicine and Professor of Radiology at Stanford University. He's going to be giving us a lecture today titled "Diagnostic Molecular Imaging for Prostate Cancer in the United States: A Focus on Lesion Localization and Distribution Using ¹⁸F-DCFPyL at Biochemical Recurrence". So, welcome, Andrei.

Andrei Iagaru: Thank you, Dr. Koo, and thank you to the panel for the invitation. I'm honored to be part of the group, and I look forward to our conversation. 2020 has been a terrible year in so many ways for us at Stanford, in particular, because we lost a really good colleague, mentor, friend, and the reason why many of us chose nuclear medicine. So I'm dedicating this talk in honor of Sam.

Despite all the bad things that happened in 2020, 2020 is also a year with significant progress in the field of molecular imaging and theragnostics for prostate cancer. So I'm going to spend a little bit at the beginning presenting what molecular imaging can do overall in this field. But then the most important part of the talk will be focused on DCFPyL.

Unfortunately, prostate cancer remains the number one cause of new cases in the United States in men, and second only after lung cancer as far as deaths, and this did not change for many years. It tells us that we need to do more, not only to treat but also to diagnose early and to diagnose accurately prostate cancer. And hopefully, play a role in the treatment as well. There's a myriad of treatments for prostate cancer, but I think that nuclear medicine is finding its way in this scenario.

I borrowed this slide, and I added at the bottom where I think that there are opportunities for us to have an impact. So at the early stages prior to diagnosis, prior to surgery, prior to focused treatment such as HIFU or HDR brachytherapy, I think that the combination of MRI with its unique anatomical abilities to identify soft tissue disease with PET in PET/MRI will be uniquely positioned to help.

Following down the line in the progression of disease, I think that one can make an argument for either PET/MRI or PET/CT, PET/CT being a faster examination, PET/MRI having some advantages for the pelvis. At later stages of disease, PET/CT will be the way to go mainly because the disease is extending beyond the pelvis. And also because the duration of the exam, particularly with digital scanners, can be cut significantly on the order of a few minutes only.

And for the general public who perhaps did not see some of these machines, this is how PET/MR, PET/CT, or SPECT/CT look like. They combine the anatomical information from MRI/CT with the functional information from PET or SPECT, all in one exam. We see images co-registered, and in the case of PET/MRI, truly simultaneously acquired.

As far as nuclear medicine and prostate cancer, let's not forget that we still have FDG and sodium fluoride. FDG is the workhorse in many of the Nuclear Medicine clinics in the United States. Although FDG is only utilized in advanced cases or in cases of aggressive prostate cancer, it's something that can be useful. It's also cheap compared to other tracers and the same is true for for sodium fluoride. So we have access to these FDA-approved, and in certain patients, they make perfect sense to be used.

Fluciclovine, commercial name Axumin®, has been introduced clinically after the FDA approval in 2016. It targets amino acids transporters and it is not specific for prostate cancer. This amino acid transporters expression is increased in other instances as well. This is the normal biodistribution. You start imaging really soon after the injection, three to five minutes later, to avoid uptake in skeletal muscles later on. It has liver metabolism. It has uptake in the pancreas. It has the advantage of minimal excretion in the urine, so the pelvis can be easily evaluated. It has low grade bone marrow uptake and a few other areas of uptake as illustrated here.

Fluciclovine has been very useful since its introduction in 2016. Here are different patterns of disease recurrence: on the left, nodal disease in the pelvis, in the middle, nodal disease extending in the retroperitoneum as well as the bone metastasis in the right femoral head. And then the example on the right, extensive bony metastasis in this patient. There are publications indicating that fluciclovine will not compete with PSMA, will not be as sensitive, as accurate. But I do maintain that in selected patients, Axumin® will continue to be useful.

This is our experience from a paper under review currently (now published) evaluating 165 patients who were referred to our institution for axumin after the approval. And you will see what's interesting the mean PSA is quite low, actually. It's 3.1, which tells me that our referring physicians, courtesy of many presentations at meetings and the published data, are sending these patients to us earlier when biochemical recurrence is suspected. So we have cases at PSA very, very low as 0.02 ng/ml illustrated here, and then they span the entire spectrum of disease from more aggressive to less aggressive. What's interesting here, it's the fact that more than half of these patients were scanned on a digital scanner and I will come back to that here.

So if you look at the positivity rate based on PSA quartiles, the numbers that are reported here are slightly higher than what's published in the literature. And I think that this is due to the fact that more than half of the patients were scanned on a digital scanner. So it's not just progress of the science of radiopharmaceuticals, its recent progress in technology, all vendors currently offer digital PET/CT scanners, which provide increased image quality, which in the end leads to higher sensitivity and improved lesion detection. So let's not forget about fluciclovine yet. Despite all the excitement with PSMA, I do believe that fluciclovine will have a role to play, albeit a smaller one. And of course the more aggressive the cancer, the faster the doubling time, the higher the positivity rate as illustrated here. And I'm referring here and in the remaining of my talk to positivity rate. Since we're not able to biopsy all the lesions, I don't think that we can launch into other statistics. Our clinicians trust these images. And they only biopsy in selected cases where the pattern of distribution does not make complete sense.

And here are a couple of examples. This patient who has a medical history as provided here, had rising PSA at the time of the scans, 3.2 ng/ml, and we identified this area of uptake in the prostate bed. This was biopsy-proven to be recurrent disease. This is another example, one that I used to illustrate that fluciclovine is actually useful. This is a low PSA, 1.24 ng/ml. And here in the top row, we're able to see tiny pelvic lymph nodes in the obturator space and the peri-rectal fat, as well as a tiny, osseous metastasis in the left pelvis. So again, not every case looks like this, but there are cases where fluciclovine can be very useful, even at low PSA values.

But you go to any meeting, whether it's imaging (and RSNA just ended last week), but I'm very happy to see that at ASCO and AUA, there is a lot of buzz about PSMA and rightfully so. Because this is something that I do believe already changed the practice of how these patients' prostate cancers are managed in many places, including in the US, and the future will bring significant improvements in patient care based on this.

This is a normal biodistribution of agents used at my institution. We started using PSMA-11 in early 2015, and we switched to DCFPyL in 2018. Regardless of the two, the biodistribution is very similar with uptake in lacrimal and salivary glands. And some uptake in the liver and spleen. These tracers bind to the kidneys and they're also excreted in the urine. That's why we see kidneys and bladder, and there is some uptake in the bowel. I acknowledge that other PSMA traces like PSMA-1007 have less renal clearance, which may be advantageous for evaluating the prostate bed. However, they do have higher liver uptake and they have a higher rate of false positives as reported in the literature.

These are patterns of prostate cancer lesions on PSMA imaging. So on the left, a few lymph nodes in the pelvis, in the middle, more extensive nodal disease, and then on the right, nodal disease as well as multiple bony metastases.

Although this is not a topic of my talk, I do believe that PSMA PET will change the practice of how patients are managed prior to surgery, particularly for intermediate- and high-risk patients. And this is data from our publication, and you can appreciate the diagnostic accuracy of PET compared to multiparametric MRI in this cohort. And this is not to say that PET will replace MR. MR provides very, very useful information for the surgeon, but what I think will happen, we no longer need to have, I don't know, 5,000 MR images in each patient. Probably we can eliminate some of the sequences that are used because PET is able to provide the information that's needed to accurately interpret these images.

And let's take a look at a couple of examples. Here is one. We always acquire first fast, whole-body PET/MRI to look for distant metastases. And then we do a dedicated PET about 20 minutes at the time when the prostate MR images are acquired. The PET is always on in this PET/MR system, so you get high-quality images. And these images most of the time are really easy to interpret as it's illustrated here. You have two areas of focal uptake in the prostate, in the posterior peripheral zone bilaterally. And our surgeons are taking the prostate out, and then they're sent to pathology in a 3D mold based on the MRI done prior to surgery. And then they're sectioned, the cancer is marked, as you can see here, correlating very nicely with imaging. And actually, these pathology slides are now sent to PACS. So we have access to imaging from PET, from MR, and after surgery to pathology. There's also very interesting work done by some of my colleagues to co-register for biopsy guidance, as well as for treatment planning with high intensity focused ultrasound and with HDR brachytherapy. So a lot more to come.

Now, this is another example. Again, easy to interpret images, focal uptake in this case in the right posterior prostate, and it correlates very nicely on pathology with where the cancer was marked by our colleagues.

But I'm here to talk to you about our experience with ¹⁸F-DCFPyl PET at biochemical recurrence of prostate cancer. As I indicated earlier, we started using it in 2018 through a research access program through the Prostate Cancer Foundation. So I acknowledge their support, as well as Progenics' support for this program. So the patients have to fit entry criteria, but we waived the professional and technical fees, and so there are no charges sent to patients for this exam at our institution.

This is data from this initial cohort of patients. Again, a variety of Gleason scores of patients, a variety of prior scenarios, radical prostatectomy, majority of the patients, but also radiation therapy and some received hormonal therapy as well.

These are again the positivity rates per quartiles in the top table. And you can see that once you get to a PSA higher than 1 ng/ml, you get into positivity rates of greater than 90%. So I think that really we can identify disease at very early stages of recurrence when you can, hopefully, have a meaningful impact as far as treatment. So it's no longer the case that we are unable to identify where the PSA is coming from. Even at a PSA less than 0.5, 68% positivity rate is really high. Now we're punting the issue back to our colleagues in med onc, rad onc, and urology. How do you treat these patients? And I'll show you some examples with very minimal disease and it's upon us to identify the best management for these patients. And as I stated earlier, the more aggressive, the faster doubling time, the more positivity rate we'll find in these cases.

Where do we find these lesions? So in the top table, post-prostatectomy, majority of these are lymph nodes in the pelvis and extra pelvic locations, but also some patients present with dominant bony disease and as well as other organs. Most commonly in our experience, being the lungs, but also the liver. And similarly, we can appreciate after radiation therapy, there is a higher proportion in the prostate bed, not unexpectedly, I would say. But then lymph nodes and bony metastases are the most common sites of recurrent disease.

What's interesting in our experience, if we count oligometastatic disease, we counted it as one to three lesions. I'm not arguing that this is the only way to count it, but you can appreciate that in this cohort of close to 190 patients, 14% had recurrence only in the prostate bed, so you can do salvage local treatment. And then 25% of the cohort had only pelvic disease. So again, perhaps salvage radiation therapy. And then another cohort of patients had extra pelvic oligometastases. There are probably other sites of disease that we are unable to identify. So perhaps the salvage therapies are not the only way forward. They need to be combined with other tools in the armamentarium. But definitely, we are able to identify disease at earlier and earlier stages that will allow treatments that perhaps can even have a curative intent.

And here we come to the impact of PyL on patient management. Treatment was changed in 60% of the cases that were seen at my institution in this expanded access program. And we do have now a protocol with questionnaires. We send a questionnaire to the treating physician prior to the PET, and we send them the questionnaire back after the PET trying to identify what happened. And here changes were made to radiation plus/minus hormonal therapy or monotherapy alone or surveillance. For about 16% of the cases, we did not have all the data available. And what's interesting, some patients received empirical treatment even with negative PyL, which is something that I would hope will happen less and less, but it is the practice of medicine.

And here are some examples. This is a patient with a PSA of 5.4 and you'd expect more disease. But what we've seen were tiny pelvic lymph nodes. This is another example. In this case, PSA of 0.4. So low PSA, and there are tiny bony metastases located in the spine and ribs as well as in the pelvis. And I'm showing the one in the right ischium, a very small lesion, but very accurately identified, very conspicuous on these high-quality PET images.

This is another example. Some of these patients have a sodium fluoride PET at the same time. The red arrow is pointing to a lesion in the right ischium that identified on both scans. The green arrow is identifying a tiny lesion that's only seen on sodium fluoride. So although the literature and our experience support the fact that PyL PET will likely replace bone scintigraphy in most instances, there will be occasionally patients who would benefit from having bone scans as well. But the way we sequence bone scanning probably will change post PSMA approval.

This is yet another example. We see relatively low PSA, 0.7. In this case, we have pelvic lymph nodes, but also we have a left supraclavicular lymph node. So like with other malignancies in the abdomen and pelvis, the migrations within the lymphatic channels lead to the left supraclavicular lymph node, which of course in the gastric cancers is known as the Virchow's node. This example also illustrates a false positive over the right hemothorax. There's some uptake that's actually uptake in the rib and that's actually uptake in a site of fibrous dysplasia. So prostate-specific membrane antigen is a great misnomer, as it is not prostate-specific. It is over-expressed in a majority of prostate cancers.

I'm going to show you some examples now where fluciclovine was also done, not to make the case that fluciclovine is always negative, but in this case, the case I've just shown you with lesions seen, pelvic, retroperitoneal lymph nodes, as well as in the left supraclavicular space. There is no uptake in these areas on fluciclovine.

Here is another example, a 68-year-old man with low PSA. This patient had the metastatic disease in the abdominal wall that was previously treated. You can see the markers from the prior treatment. And now there is focal uptake at the edge of the treated area. And this was proven to be a recurrent disease in the treated field.

And just like we see in other examples, the Axumin® was negative. And our workflow is currently that patients get Axumin® (fluciclovine) because it's FDA approved and the insurance will reimburse it in most cases. But if the scan is equivocal or negative or if it doesn't correlate with the level of the PSA, then these patients are referred to the research access program for PyL. Hence, this bias towards patients with negative fluciclovine and positive PyL in this cohort that I'm presenting.

This is a dramatic case of extensive disease in the skeleton, as you can appreciate here, as well as uptake in pelvic lymph nodes. This patient, interestingly, had sodium-fluoride prior to the PSMA scan. And although it identified disease, it did not pick up the true extent. And also it obviously did not pick up nodal metastases because we don't expect them to be identified on a bone scan.

And I will show these as the end as some of the most dramatic cases. These scans were done within one day of each other. And although I think that an experienced reader will call the bone scan positive diffusely, like a super scan, the true extent of disease in the skeleton that is noted the next day on PyL, it's really dramatic.

And so I will end with this slide. Here on the left, the same patient, fluciclovine, gallium PSMA-11, showing some retroperitoneal lymph nodes. And then three days later, this patient got a PyL that identifies more pelvic and retroperitoneal lymph nodes. So these three scans were done within a month of each other. And the PSMA-11 and PyL were done within three days of each other. And it's not always the case that PyL identifies more lesions. There are other factors into play, the quality of the scanner, et cetera. But given the physical properties of F18 image quality, I think PyL will be superior. It remains to be seen if it will lead to more lesions being detected in a majority of patients, but it is definitely easier to distribute commercially.

So I will end with a few things from our own research. Other targets exist; as good as PSMA is, and I think it's really excellent, we're not dealing with physics here. We're dealing with biology, and biology has many ways to mess up with you. And prostate cancer is no exception from that. So we need in our armamentarium more targets and bombesin is targeting gastrin-releasing peptide receptors that are over-expressed in 60 to 100% of prostate cancer, depending on data in the literature. The biodistribution of one of these agents, gallium 68-RM2 is shown on the image on the right and you see there's no uptake in lacrimal or salivary gland. This is pretty much nothing above the diaphragm, much less hepatobiliary clearance, and there's no binding to the renal cortex. There's renal excretion, but no binding to the cortex. These gastrine-releasing peptid receptors are overexpressed in the pancreas, hence the high uptake there. But the pancreas is radio-resistant and there is no toxicity from diagnostic, or even from therapy versions of these peptides.

And here at the top, you can see from our experience of about 50 patients who had both PSMA and RM2, different examples. The one on the left, more lesions on PSMA than there are on RM2. The next one, more on RM2 then on PSMA. The other one, more bone lesions on RM2 than on PyL. And then the one on the right, negative RM2, but multiple bony lesions on PyL. The positivity rate is slightly lower than with PSMA in our cohort, more than a hundred participants to date. However, it gives an option of having another tool in our armamentarium if PSMA is equivocal and perhaps in negative cases.

So this is something that I added to what's already out there. It's my wish list. My wish list came true with PSMA-11 approval last week, and we expect the approval of PyL next year. And let's hope for lutetium-177 therapy versions of PSMA. And then a few years later, I do hope that one or some of these agents targeting gastrin-releasing peptide receptors will also be approved. They also can help in breast cancer and other malignancies.

I want to acknowledge my colleagues. Research is a team sport, and none of this work could be done without having a great partnership, not only in nuclear medicine and radiology, but most importantly, working as a team with medical oncology, radiation oncology, and urology. With that, I thank you for your attention, and I look forward to our conversation.

Discussion

Phillip Koo: Hello, welcome back. We've heard a wonderful lecture from Andrei Iagaru about PSMA imaging focusing on PyL. Very fortunate to have with us my esteemed colleagues Dr. Alicia Morgans and Dr. Neal Shore, who are very familiar to all of us. We're going to sort of have a multidisciplinary discussion about the impact of PSMA on all of our different practices, and how we might be able to utilize this tool to benefit our patients.

First I want to start with a question to Alicia before she has a chance to ask a question of Andrei. Alicia, from a medical oncologist's perspective, clearly something like this is going to change the type of patient you might see in your clinic. You might start seeing patients with M1 disease, or maybe even visceral metastatic disease that were non-diagnosed pre-PSMA. How do you expect all this to shake out? Because I imagine there's going to be a lot of "chaos" during this transition period.

Alicia Morgans: I completely agree with you, and I think we're going to have to think about where these patients used to fit as we try to understand where they are. So I see patients with localized disease sometimes, some with biochemical recurrence and some with what we would consider very low volume or oligometastatic disease, and these are the areas where I see probably the most disruption. So when we see patients that we think have localized disease, and I'm advising them about, do you want to do surgery or do you want to do radiation, because sometimes people ask medical oncologists that, to be sort of neutral advisors in those decisions, and if we start to see areas of oligometastatic disease, that's going to change our recommendation. I may encourage people to think about maybe radiation, and maybe intensified systemic therapy in addition to SBRT, to lesions for example. Do I know that's right? No, I don't, and so that's where we get into sticky situations. Maybe that patient should still have surgery, and then maybe he should have radiation on top of that, and then SBRT on top of that with systemic therapy, and that might be a direction we go too.

I can see this happening in each of our disease states, we don't need to go through each of them, but I think it's going to cause each of us to think a little bit more critically about how we advise our patients, certainly. But it's also going to bring to the fore the necessity that we need to have trials that actually answer these questions. Because I can say one thing or another, Dr. Shore you could say some completely different message to these patients, and neither of us will know if we're right or not unless we actually do the studies. So I think that's how I view it, and I appreciate people like you nuclear medicine physicians, who can help us see what we're missing, and then design the trials around those patients.

Phillip Koo: Thanks Alicia, that's very insightful. If you have any questions for Andrei, please go ahead.

Alicia Morgans: Yeah. I think one of my biggest questions, sort of springboarding off of that. I think as medical oncologists we feel like we've got some very clear Phase IIIs that help us understand how to best use our therapies. One of those areas that's been relatively newly developing has been the non-metastatic castration resistance setting, and one of the biggest challenges that I have with that particular setting is that we know that those patients aren't non-metastatic. They're just non-metastatic by conventional imaging. And the other piece of that challenge is that we also know that intensified systemic therapy can help these patients live longer.

So when I'm faced with patients who have PYL PSMA positive disease for example, from your perspective, how should I best advise those patients? Should we think about using a metastasis-directed approach to delay time to additional systemic therapy? Should we think about compounding or intensifying our systemic therapies and also use metastasis-directed therapy? Do we do nothing until we have further clinical trials? What do you think?

Andrei Iagaru: I think that doing nothing is not an option, right? Patients are unlikely to accept that. But I can see the dilemma. As I said in my talk, we see probably the tip of the iceberg. If we see those lesions, there are other lesions that are below the performance of our imaging. So metastatic-directed therapy alone, I don't think would be the answer. I think we'll need the combination.

There are also other advances in technology, such as biopsy-guided radiation therapy systems. The new one from the company called RefleXion, it's using the PET signal to guide the radiation beam. And that can do, in one instance, more than one treatment for one metastasis, it can do multi metastatic disease. So you can use a combination of systemic therapy, external radiation, internal radiation. As you said, we need to learn how to combine these. It's very great now I have so many options.

And if I may make a small comment, I hope that in the future PET will also be conventional, because I don't think it's unconventional anymore. It's been around for many years, and it provides information that anatomical, morphological information cannot. But it's not unconventional. And it's on us to show that it's a conventional method.

Alicia Morgans: I love that. We need to bring our nomenclature into the future too, or into the present actually, right. Thank you.

Phillip Koo: That's a good point. Conventional imaging, next-generation imaging, I think all these terms are going to sort of fade, especially now that we have FDA approval for gallium 68 PSMA.

So, Neal, it was interesting, with the approval of the gallium 68 PSMA-11, it was the first time now we've had one of the PET radiopharmaceuticals approved for initial staging. I imagine that has sent some shockwaves in the urology community. Can you speak to that? And then feel free to ask Andrei a question that you might have.

Neal Shore: Thank you for that question, Phil, and thank you, Andrei, for a wonderful presentation. I learned so much, and the specialty of urology is about to learn a tremendous amount thanks to the work that you're doing, Phil's doing, and other nuclear medicine radiologists. In the US there's a bit of a disconnect, I think, compared to our European colleagues, where nuclear medicine radiology as a specialty is very involved in therapeutic decision-making. I think we see that prominently in academic centers in the US, less so in the community. So I'd like you maybe to both comment on that.

One of the things that you touched upon was, with these more accurate, greater sensitivity scans, RM2, ¹⁸F PYL, PSMA gallium. We're seeing many more lesions. As someone who does a lot of clinical trials, one of the things that I find a bit disconcerting is when I get a traditional technetium bone scan, and my radiologists report back, "It's too numerous to count." I know there's some new software, artificial intelligence programs, that are better at estimating that. That is obviously of importance as we are doing clinical trials, or move from one line of therapy to another. So those two questions, where will nuclear medicine radiology evolve in 2021 and beyond in the US, and then this other issue regarding the importance of not using that term, "Too numerous to count."

Andrei Iagaru: Neal, both excellent questions. Let me tell you about the experience of my institution. We now see colleagues in urology prostate tumor board every other week, where the cases that are referred to these programs for pre-prostatectomy imaging are reviewed together. Then of course we have the other tumor board with our colleagues in med onc and rad onc for the post-initial treatment setting.

So I think that if we want to be recognized and have a seat at the table, we need to be engaged with other doctors in tumor boards in multidisciplinary conferences. If we sit in silos it's not going to be good for any of us, and most importantly it's not going to be beneficial for the patient. So I fully agree with you, it needs more effort. And I'm proud to say that there are more and more activities in this direction.

It was recognized a number of years ago, at SNMMI as well as RSNA, that the radiologists and nuclear medicine physicians have to get out of their reading rooms and show their faces. We had a program at my institution where we were meeting with the patients after their scans and answering their questions, et cetera. So it's a multi-pronged approach: be more visible in multidisciplinary tumor boards, be more visible to the patients.

The other question, about "too numerous to count," I hate that term, although occasionally I use it because they are indeed too numerous to count. I think that artificial intelligence, and coincidentally AI are my initials, is something that we will lead with. I'm not threatened by it, and I think that the majority of my colleagues are not threatened. Only those who will not adopt AI and machine learning will be threatened. Otherwise, it will make our life easier. There's no way that we can hire enough people to read all the scans that will need to be done. There's no physical space for offices to put those people, where would they read it?

So I look forward to the work from artificial intelligence to classify reports into likely normal, likely abnormal, to categorize the lesions. It will not replace us, it will make our lives better. It will make our reports better. PyL will come with a software, most likely, that will assist physicians in image interpretation and reporting. There is progress being made there. So I hope that when we talk again in the not too distant future, you will be happy with what you will see as far as implementation of these techniques in how we review data, and how we report out.

Phillip Koo: Great, thank you. I have two questions. Number one, briefly can you talk about access to PSMA today, and what it might look like in the next six months or 12 months? And number two, do you have a PSA cutoff at which you would recommend a PSMA PET-CT in a patient at biochemical recurrence?

Andrei Iagaru: Thank you Phil, both great questions. Everyone is excited by the FDA approval for PSMA-11, gallium 68 PSMA-11. And it pertains to UCLA and UCSF, so they did a great job to get this approval, and they kindly waived the exclusivity rights, meaning every other center can file an abbreviated new drug application. The problem is that it takes the FDA up to two years to review this abbreviated new drug application, so it's not helpful outside of these two institutions.

The Society of Nuclear Medicine and Molecular Imaging has on its website a posting that very accurately describes locations in the US from the clinicaltrials.gov, that have research access programs or research programs offering PSMA-11 and PyL for the patientz. They still need to fit the inclusion criteria. Some offer it at no cost to patients, some operate at out of pocket cost to patients, but there are options. The good news is last week also, both Lantheus Progenics, as well as Telix, put out press announcements that the FDA accepted their new drug applications for PyL, as well as for PSMA-11. We expect PyL approvaal, it has a date of review at the end of May and soon after PSMA-11. So let's navigate the next few months, and then our patients will have access to PSMA extensively.

So did this answer your question?

Phillip Koo: Sure. Oh, the PSA level for biochemical recurrence?

Andrei Iagaru: And the PSA level. I think that Alicia was saying earlier that we need to reeducate ourselves as to what is biochemical recurrence. I don't think that the current AUA and ASTRO BCR criteria will be valid anymore. We've seen positive scans at PSA values less than what currently would be defined as biochemical recurrence. So I don't necessarily have a cutoff right now because I frankly don't know which one to use, but I do know that what's currently widely used is no longer accurate, because with PSMA imaging we find disease at lower values of PSA.

I also think very strongly, based on what I've seen in our experience with both PSMA and bombesin, things that are markers of tumor aggressiveness like velocity, PSA velocity, doubling time, should be integrated in the algorithm. Because if you find lesions in a cancer that's not aggressive, should you really jump into being aggressive and treat? Probably not. Versus, let's find out the cancers that are really aggressive, and where if you intervene you can have an impact on overall survival. I think that that's the next step for us. And I will quote from a colleague, very experienced in nuclear medicine, Rod Hicks at Peter Mac in Melbourne. He's like, "We don't want to count lumps, we're not into lumpology." We want to make meaningful diagnoses that will have an impact on overall survival. That's the next step.

Phillip Koo: Great. In the spirit of the holiday season, with the couple minutes that we have remaining, maybe we'll go around and briefly give one wish that you have for the prostate cancer community in 2021. Kind of a vague question, but maybe I'll start.

My wish would be, it'd be wonderful to make some progress when it comes to the lutetium-177 based therapies in the upcoming year. Alicia, I'll turn it to you.

Alicia Morgans: Sure. I wish that we expand access for patients to these imaging modalities. As we heard from Andrei, it's fantastic that these things are available at UCSF and UCLA, but I treat patients in Chicago and Neal treats patients in Myrtle Beach in South Carolina, and we need all patients to have access so that all patients can really make decisions that make sense for them. So I wish that we expand access.

Phillip Koo: Neal, how about yourself?

Neal Shore: I agree with Alicia. I think accessibility is really, really important. Andrei, you began your presentation by saying one of the silver linings of 2020 during the pandemic was the demonstration that clearly the US, from a diagnostic imaging standpoint, is going to catch up with many other areas of the world that have PSMA PET. But if I could ask you, accessibility is important for me, and I would ask you, six-seven months from now, where we have approval for ¹⁸F PYL and PSMA PET, and you're a center within the US looking forward to starting this, what are the differences, just logistically, in picking one of these modalities versus the other?

Andrei Iagaru: Neal, that's a great question, and Alicia, great comment. I will make it very clear. In addition to what's FDA approved at UCLA and UCSF, there are multiple centers throughout the US where patients can get PSMA in research programs or expanded access programs. So don't give up, those sites are listed on clinicaltrials.gov. Our site is one of them, there are many others. So everyone is making efforts to have this fantastic tool available for patients. It's not where we want it to be but we're getting there.

I think, to answer Neal's question, that academia can only do that much. I think that for the wide availability of this new method, the industry has to step up. And the industry partnering with professional societies to educate the physicians, it will do no good if this is widely available and you don't have a workforce that can appropriately interpret the images if you get too numerous to count, to quote from your earlier comments. And there are efforts going there.

So if one wants to start from scratch, first find out what commercial radiopharmacy is available in your area, find out when they will start the PyL or PSMA-11 programs, educate your workforce. There will be webinars, there will be meetings where people will learn how to interpret those images. It's not very difficult but you need training, you need appropriate training.

Then also, work with your billing and compliance to make sure that actually these are paid by insurance, and the patients don't end up with bills that will be difficult to pay. So those are, in my opinion, the three ways. Educate the physicians, educate the commercial radiopharmacies, educate your support staff.

Phillip Koo: All right, Andrei, your one wish, and that's the last word.

Andrei Iagaru: You made very good wishes, all of you. I will say, in addition to what you said about getting approval for lutetium PSMA, let's move into earlier stages of disease. I understand the approval will be done at late stages to get your endpoints, but let's move it up to earlier stages of disease where we're not palliative, we're not prolonging survival by a few months, where we can have a more meaningful impact on overall survival, in combination with other treatments.

Phillip Koo: Wonderful. Thank you very much, it was great talking to you, and I thank you all for your time today.

Alicia Morgans: Thank you.

Andrei Iagaru: Thank you.