Activity Transcript

Paul L. Nguyen, MD: Hi, everyone. I'm Paul Nguyen. I'm the Baldwin-Politi Distinguished Chair in Oncology, professor of radiation oncology at Harvard Medical School, and vice chair for clinical research in the Department of Radiation Oncology at Dana-Farber/Brigham and Women's Cancer Center in Boston. Welcome to this program titled, "Refocusing the Image: Diagnostic Imaging Within Prostate Cancer." We are so excited and so fortunate to have with us today 2 incredible speakers to share their knowledge with us. First, I want to welcome Dr Jerry Andriole, professor and director of the Brady Urologic Institute in the National Capital Region at Johns Hopkins University. Welcome, Jerry. We also have Dr Andrei Iagaru, professor of radiology and nuclear medicine and chief of the Division of Nuclear Medicine and Molecular Imaging at Stanford Health Care in Stanford, California. Welcome to you both.

Today we're going to talk about novel imaging in prostate cancer. We know that in subsets of patients with prostate cancer, standard-of-care imaging modalities might not adequately localize and characterize occult disease. These subsets include patients with biochemically recurrent prostate cancer who have low prostate-specific antigen (PSA) levels and patients with newly diagnosed high-risk prostate cancer who have locally advanced or micrometastatic disease. We need novel imaging to figure out exactly what risk group these patients are in.

We are going to focus a lot today on prostate-specific membrane antigen (PSMA). We know that PSMA is expressed abundantly on prostate cancer cells. The degree of PSMA expression positively correlates with tumor stage. Because there is high PSA expression on tumor cells but minimal expression on tumor tissues, attaching this radioactive ligand to PSMA-targeted molecules might allow us to more accurately image or stage prostate cancer. In recent years, this approach has produced significant improvements. We're going to talk about those today.

Things we want to talk about are the clinically available positron emission tomography (PET) radiotracer used for imaging prostate cancer, safety and efficacy data associated with PET tracers, and how we select the most appropriate patients with prostate cancer for PET imaging. Dr Andriole, would you be able to kick us off? I know we don't talk a ton about choline-based agents and sodium fluoride anymore but give us a little bit of information on those.

Gerald L. Andriole, MD: Paul, it's been a very long journey to get to where we are today, where basically fluciclovine and PSMA seem to be the best agents. In the past, there were C-11 choline, C-11 acetate, fluorodeoxyglucose (FDG), and sodium fluoride bone scans. I think, for the most part, these are of historical interest only for everyday practicing urologists and radiation oncologists.

Dr Nguyen: Thank you. Andre, do you want to say a word about that?

Andrei H. Iagaru, MD: Yes. I agree. In many instances, this will be replaced. If there is a remaining role for the sodium fluoride bone PET, you can learn more. There are various publications and guidelines on how to do these studies. Similarly, there is a role for FDG in that small subset of patients with very aggressive prostate cancer. As we will probably learn later in this conversation, there may be other roles for FDG in selecting patients for PSMA treatment.

Dr Nguyen: Fantastic. Before we get into PSMA, which is going to be the bulk of today's discussion, do you want to talk a little about F-18 fluciclovine, Andrei?

Dr Iagaru: Sure. Fluciclovine was approved by the FDA in 2016. It's an imaging protocol. An important difference from other radiopharmaceuticals is that we inject the drug with the patient on the scanner table because you need to start imaging within 3 to 5 minutes after injection. Why is that important? It's important because biodistribution is altered after that, with more of the tracer going into skeletal muscles and thus making it more difficult to identify prostate cancer lesions.

We start imaging with the PET, going from the pelvis toward the head. That's how it's done. We need to be aware of the normal biodistribution. There is normal uptake in salivary glands, skeletal muscles, liver, pancreas, and spleen. What's important here is that there is minimal, if any, genitourinary clearance, so it's barely seen in the kidney and bladder. This has advantages, as we will discuss later on.

The bone marrow has normal optics and is actually used as a marker or threshold of positivity for these lesions. Like everything else, biologically, there will be uptake in normal tissues, and pattern recognition -- knowing where the prostate cancer has spread -- will be very important for image interpretation. There are various patterns of spread: pelvic nodal disease, prostate bed recurrence, nodal and skeletal recurrence, and visceral recurrence.

Many studies evaluated fluciclovine in clinical use for its approved indication for biochemically recurrent prostate cancer. In our own experience post-approval, in a large number of patients, we noted positivity rates that are in line with what is out there in the literature. For a PSA level under 0.5 ng/mL, there is a relatively low positivity rate of less than 30%, increasing to about 50% for a PSA level between 0.5 ng/mL and 1 ng/mL. Then, as you go to different or higher PSA quartiles, the positivity rate is as high as 90% for a PSA level greater than 5 ng/mL.

What's also important, regardless of the radiopharmaceutical used, is the fact that using a high-end, modern, digital PET/CT scanner significantly improved the detection rate, particularly for small lesions and particularly for low PSA values. An example of the utility of fluciclovine in patients with low PSA values is shown in this slide, revealing the presence of not just nodal recurrence in the pelvis but also tiny bone metastasis in a patient with a PSA level of 1.2 ng/mL. Fluciclovine remains a useful test even in the current age of PSMA. The sequencing of how we image and when we image with one vs the other, however, is of great interest to the world.

Dr Nguyen: Fantastic, Andrei. Thank you very much. This leads us into the EMPIRE-1 study, which I want to touch on briefly. It's very exciting for radiation oncologists, and I think for everyone, because it is the first randomized trial that shows PET imaging can actually improve clinical outcomes. This study by Dr Ashesh Jani was published in Lancet and looked at patients with a rising PSA level after prostatectomy who were randomly assigned to either standard radiation per the physician or to a fluciclovine scan that would be used to guide radiation.

What was found in this study that was very interesting was that the fluciclovine scan changed the treatment paradigm for a significant proportion of the patients and, more importantly, randomization to fluciclovine improved 3-year event-free survival. Those patients for whom a fluciclovine scan was used to guide their radiation had significantly better 3-year event-free survival than those patients who did not have a fluciclovine scan. This is important because we're always asking, "Do these imaging agents actually improve outcome?" With the EMPIRE-1 study, we now have evidence from a randomized trial. 

An interesting question that may be answered next is if fluciclovine scans do such a great job, can we do even better with PSMA scans? That's what the EMPIRE-2 study is looking at. It's randomly assigning people from this patient population to fluciclovine or PSMA. Does either of you have any thoughts about that EMPIRE-2 study?

Dr Andriole: Yes. I think it will be a very important trial because, as we're going to talk about later, there may well be an advantage to using fluciclovine to identify local recurrences. If that holds up, it may allow the best form of targeted treatment for the patients. It's really a trial that's necessary, in my view.

Dr Iagaru: I would briefly add that there's always a better trial design that may be out there, and we're seeing the limitations of trial logistics. One can imagine maybe a better-powered study for survival in EMPIRE-2 or maybe randomly assigning patients to get both and then picking out treatment based on the scan that identifies more disease. But I agree with what you both said: it is very important for us to learn how to use these penetrative pharmaceuticals for radiation treatment planning and to determine what impact, if any, they have on survival, which is the most important thing for patients.

Dr Nguyen: Next, we're going to talk about PSMA scans, which is what we're going to focus on for the rest of the discussion. Andrei, do you want to kick us off with talking about PSMA?

Dr Iagaru: Absolutely. It's my pleasure. PSMA, which stands for prostate-specific membrane antigen, is a transmembrane protein that's overexpressed in most but not all prostate cancers. It is a carboxypeptidase with known enzymatic activity. We now have 2 FDA-approved radiopharmaceuticals in the United States. The FDA approved gallium 68-PSMA-11 in December 2020 first for use at the University of California, Los Angeles and University of California, San Francisco, and then in December 2021 as part of a kit that will be available nationwide. 18F-DCFPyL was approved in May 2021 and is available nationwide.

The biodistribution of these illustrates that although we call PSMA prostate-specific, it is really not prostate-specific. It's overexpressed in normal tissues, such as lacrimal and salivary glands. It binds to the kidneys and has some renal excretion, as well; and low-level uptake is seen in the liver and spleen and throughout the bowel. The pattern of spread with prostate cancer can be easily identified with PSMA. Again, pattern recognition is what we use in imaging. Knowing the pearls and pitfalls, normal bowel distribution, and false positives are very important for interpreting these images. The bulk of these scans are done using PET/computed tomography (CT). Imaging starts about 1 hour after injection of either radiopharmaceutical, and you can do it with or without intravenous or oral contrast.

If PET-magnetic resonance imaging (MRI) is available, it is a perfect tool for the pre-prostatectomy setting, where you get the best of both worlds. You get ideal soft-tissue delineation from MRI, as well as the high value of PSMA in 1 exam. Various protocols can be used in that setting, which, in the interest of time, I'm not going to go into. With both Ga 68 PSMA-11 and 18F-DCFPyL, we have FDA-approved indications for prior to definitive treatment and for biochemical recurrence.

In our experience, the addition of PSMA-11 to PET in patients with intermediate and high risk prior to prostatectomy yields higher sensitivity and aids detection of local and distant metastasis in a proportion of cases. There is also a lot of work going on in this space looking at the prognostic value of the uptake in the prostate gland. In the biochemical recurrence setting, it is important to understand that the positivity rate for detecting recurrent prostate cancer is higher in all the published studies. We're talking about tens of thousands of patients who have been reported on, with detection rates as high as 30% to 50% even in patients with PSA values of less than 0.5 ng/mL. There is an argument to be made that the longer you wait, the more lesions you find. However, the jury is still out there regarding that.

As with fluciclovine, it is important to use modern technology -- digital PET/CT or PET-MRI -- whenever you're looking at a patient who has a low PSA value because you will increase the chance of identifying disease. Selection bias may affect various studies. For example, if you include patients with negative or equivocal fluciclovine in your PSMA studies, many times you will find more lesions with PSMA or you'll have positive PSMA and negative fluciclovine.

There are 2 seminal studies involving 18F-DCFPyL. One is the OSPREY study, which was a phase 2/3 trial that looked at prostate cancer in the presurgical and biochemical recurrence settings. There were various rates of success at identifying disease. Of course, no imaging study will always be able to identify micrometastases (small-volume metastases in pelvic or regional lymph nodes), so sensitivity was lower in that scenario. There were, however, high positivity rates and correct localization rates for identifying disease in the biochemical recurrence setting. Results were later confirmed in the phase 3 CONDOR study that led to FDA approval of 18F-DCFPyL. The 3 central readers had very high and consistent positivity rates in detecting recurrent disease at various PSA levels: about 40% for a PSA level < 0.5 ng/mL, 50% for a PSA level of 0.5 to 1.0 ng/mL, and then more than 90% for a PSA level > 5 ng/mL. That is similar to our experience in using 18F-DCFPyL in our expanded access program, but because all our patients were scanned using a digital scanner, we had an even higher positivity rate of about 50% for a PSA level < 0.5 ng/mL. 

What will also be important is how well these PSMA agents are able to detect disease outside the pelvis in patients with biochemical recurrence and how well they are able to identify oligometastatic disease. Once again, that is a topic of future research for the field. 

Here are a few examples showing the identification of both nodal and bony disease with F18-DCFPyL at a PSA level of 0.4 ng/mL. To the point Jerry was making earlier about possibly replacing bone scans, here is an example of widely metastatic bony disease with 18F-DCFPyL that was more subtle on a bone scan than with 18F-DCFPyL PET MIP, with the 2 images being obtained 1 day apart. In brief, that is where we are with PSMA. We now have nationwide access to 2 agents approved in the setting of definitive treatment for staging and for biochemical recurrence.

Dr Nguyen: That's fantastic, Andrei. Thank you so much. I know as we're thinking about PSMA vs fluciclovine, we think about these head-to-head comparisons that you were touching on. Jerry, do you want to talk about the head-to-head studies comparing PSMA with fluciclovine?

Dr Andriole: There's no perfect study out there comparing the 2 agents, although it does appear that, by and large, a PSMA-based scan will always have a slightly higher detection rate than a fluciclovine scan. The one thing that strikes me in most of the studies out there, however, is that identification of local recurrence is always a little higher with fluciclovine than with either gallium PSMA scans. This could be very valuable to patients. Thus, even though it's probably true that PSMA-based scans have a higher detection rate for any given PSA stratum, I think there will probably still be a role in this setting for fluciclovine scanning.

Dr Nguyen: Thank you. That's a really good point we need to think about regarding local recurrences and how we may be able to see them better with fluciclovine scanning. We've gone through the data. Maybe we can now talk about some practical scenarios where we might incorporate these. Jerry, PSMA has now been approved for any patient at potential risk of metastasis. What do you do now if you have a patient with high-risk prostate cancer you were going to take to the operating room but now has a PSMA scan is positive for some micrometastases -- which you only saw on PSMA PET and not on conventional imaging? Do you still operate?

Dr Andriole: That's a terrific question, and I don't think anybody knows the answer. In general, for patients who are young, healthy, and have just a few metastases -- particularly if they're pelvic nodal metastases -- I think we should still offer surgery to those patients. It should be targeted surgery to remove the involved or abnormal lymph nodes, which are sometimes well away from the usual sites we think of for primary pelvic metastases from prostate cancer. Sometimes, they're even outside of the pelvis.

Now, just like the EMPIRE study was done to show that altering your treatments will make a difference, which in this case would be altering the extent of your pelvic or other lymph node resections, that is something we in the urological community need to establish.

Dr Nguyen: I totally agree with you, Jerry. When I think about high-risk patients in the radiation setting who have a positive PSMA scan, I would hate to deprive them of the chance to have definitive therapy because we see something on the PSMA scan. These patients were previously considered nonmetastatic (based on conventional imaging), so when we see something positive only with PSMA imaging, I don't necessarily want to flip them over and deprive them of definitive therapy. I still treat those patients. I might expand my field to include those PSMA-positive lesions, but I'll still give them definitive therapy. I'm totally on board with you. I'm not using this to deprive patients of therapy.

Dr Andriole: Yes, I agree. Treating the primary tumor in patients who have limited metastases is beneficial. If you can also treat, eradicate, or remove any of the oligometastases, that's also apt to be very beneficial to patients.

Dr Nguyen: Andrei raised a really good point earlier in our discussion. PSMA scans are now able to pick up recurrences at such a low PSA level. Sometimes, you can see lesions with PSA levels between 0.1 ng/mL and 0.2 ng/mL. What does that mean, Jerry, for our definition of PSA failure?

Dr Andriole: Well, for patients who have had a prostatectomy, it creates a lot of anxiety and havoc. The American Urological Association, for example, and many insurance companies require a post-radical prostatectomy PSA level to be > 0.2 ng/mL and rising to declare biochemical recurrence. Now, many patients use ultrasensitive PSA assays and see their PSA level rising above 0.1 ng/mL, up to 0.15 ng/mL and want to move forward with getting a PSMA PET scan, but many insurance companies won't allow it. Paradoxically, some insurance companies even require negative conventional imaging at these very low PSA levels. As we all know and have known for many years, they are virtually always negative, or, if they're positive, they're falsely positive. It's really something we need to clarify with our payers and have heart-to-heart conversations with our patients about what to do.

Dr Nguyen: That's a good point. I've certainly run into that, as well, with insurance coverage, where I can't get a PET scan until they've had a negative conventional scan twice even though they're PSA level is 0.3 ng/mL or at a range where we know we'll almost never see anything on those scans. What do you think, Andrei? Can we get to a situation where we can just replace that kind of conventional scanning with PSMA scanning?

Dr Iagaru: I think we're very close to that. The data are there. There's a nice study from Australia where they showed that the cost of doing CT plus a bone scan was higher than doing PSMA PET/CT for staging these patients, who had better outcomes with PSMA. Of course, our healthcare system is set up differently than the healthcare system in Australia, but that's a very good starting point for us to make the argument that, at least for a large proportion of patients, PSMA should replace what we currently call conventional imaging.

I also like to think that PET is now equally as conventional as CT scanning, bone scans, and other imaging modalities. But again, it's on our imaging community to convince the others that that is the case. Along those same lines, what we're seeing at our institution with the introduction of PSMA agents like 18F-DCFPyL is that it's easier to get approval for fluciclovine than it is for 18F-DCFPyL. That will take some time to change. Again, it's a matter of habit as to how these requests are approved, but I'm optimistic that we'll make inroads.

Dr Nguyen: It seems especially important when I'm thinking about a patient who's had a prostatectomy and now has a rising PSA level. We would love to get that imaging early. I'm thinking about that meta-analysis in European Urology by Perera, where the PSMA positivity rate was 33% for patients with a PSA level of 0 ng/mL to 0.19 ng/mL, which is incredible. Those are patients who are not going to be positive by any other kinds of imaging except PSMA. It's an interesting dilemma as we move forward.

So, Andrei, how about some pitfalls? I mean, is PSMA perfect? I've heard you can sometimes get some false-positive findings in the ribs. What's going on there?

Dr Iagaru: Well, nothing is perfect when it comes to biology, and neither is PSMA. In fact, it's a great misnomer, right? It's not prostate-specific. It's overexpressed in prostate cancer, but it's also overexpressed in a variety of normal tissues. We just need to be aware of that. Low-grade uptake can be seen in fibrous dysplasia, for example. A solitary bone lesion in a solitary rib prior to surgery should not preclude that patient from having a prostatectomy.

There are a ton of data emerging in this scenario. A quick PubMed search will show you that splenic hemangioma is a potential pitfall, that some lymphoma may show uptake, that neuroectodermal tumor can show uptake, etc. Again, we need to be aware of the patient's clinical scenario. We need to be aware of the normal pattern of spread of prostate cancer. The degree of uptake is also an indicator, and anatomical imaging is your best friend most of the time because it will increase your specificity. Again, for those who are interested in learning more, there are various tools available to learn how to interpret these scans. It's very important as these get distributed more widely in the community to avoid overcalling things as prostate cancer that should not be.

Dr Nguyen: That's really helpful. What percentage of primary prostate cancers don't even express PSMA?

Dr Iagaru: It's probably anywhere from 5% to 10%. There are papers that say it's more than that. You can also have false positives, even in the prostate. But I think that there are more and more data emerging that show the focality or intensity of uptake correlates with the presence of prostate cancer. Also, some studies show correlations with aggressiveness and Gleason score.

Dr Andriole: I agree, and I'm so glad you brought up using PET scans for primary imaging because there are some centers now that rely on a combination of MRI and PSMA PET imaging to plan for adequate focal therapy and to monitor patients after focal therapy. This is, as we all know, an emerging treatment option for many patients who have small volume prostate cancers. This can really be a game-changer to allow us to do it better.

There are even some circumstances where a PSMA PET scan can help guide a biopsy and can be used for local staging over and above what you would get from an MRI scan. Urologists should be thinking of these PET scans not just for biochemical recurrence or distant staging of patients with intermediate-risk or high-risk prostate cancer, but also to assess the extent of the primary tumor within the prostate, particularly if they're considering some of these other approaches for treatment.

Dr Nguyen: That's a fantastic point, Jerry. 

Dr Iagaru: I'm glad you brought that up because this is really the next frontier for PSMA. Now that we have FDA approval for these 2 indications, we need to learn where else it can be used, and those circumstances you mentioned are perfect indications.

Dr Andriole: There was an editorial in European Urology speculating that, "Boy, it's possible that the era of prostate biopsy could be over," because if you have MRI imaging of, let's say, a PI-RADS (Prostate Imaging Reporting and Data System) 5 lesion and you have a PSMA PET scan confirming that as a very worrisome lesion, is it really necessary to do a biopsy? Food for thought.

Dr Nguyen: Very interesting stuff. Well, in the last few minutes, I think we want to touch upon theranostics. Andrei, do you want to tell us a little about therapy with PSMA?

Dr Iagaru: Absolutely. Maybe I'll start by using what is now a cliché: What is theranostics? It's the concept of having a lock and a key, right? The lock is your target -- in this case, the PSMA -- and the key is the ligand to which you can attach the gallium or F-18 that will light up the disease. If you see it, then you treat it. Then you attach the more potent beta or alpha radiation such as lutetium-177 (Lu-177) or actinium-225. I wish I had come up with that explanation, but I read it somewhere, and I'm fully using it. It's used throughout the field now, and it's a good analogy for understanding what theranostics really are. If you see something on a diagnostic scan, then you can treat it.

We're fortunate now to have data from several studies using Lu-177-PSMA-617. Some of them are early-stage studies like the TheraP study, which was a study done in Australia by Michael Hoffman and colleagues. They used a very interesting approach to eligibility where they didn't just use PSMA scans. They also used FDG as a marker of tumor aggressiveness, and that had an impact on outcomes. I know we'll come back and discuss that. The larger phase 3 VISION trial showed the benefits of Lu-177-PSMA-617 at prolonging life and delaying time to cancer progression. It is not yet FDA-approved, but the data are encouraging and suggest we will have another tool for fighting prostate cancer in our armamentarium.

Dr Nguyen: Yes, it's certainly a very exciting time. Well, I know we're getting very close to the end of time here, so maybe I could ask you both for any final comments you want to make, starting with Jerry.

Dr Andriole: Well, I think this is going to usher in a whole new era in treating patients with prostate cancer. We're going to learn how to better evaluate the extent of tumors within the prostate using PET scans, we're going to have better staging, and we're going to have better targeted surgery and targeted radiation therapy. This could be a significant game-changer for our patients with prostate cancer.

Dr Nguyen: Fantastic. Andrei?

Dr Iagaru: I would say the progress that we've seen over the past decade or so has been so remarkable in the way we are able to diagnose prostate cancer. PSMA, along with fluciclovine, is definitely part of this advancement. Before we look to the future, I want to take a moment to acknowledge the past a little and the efforts of those who discovered and improved on these PSMA agents at places like Johns Hopkins here in the United States, as well as in Heidelberg and other places in Germany; and the efforts of our colleagues in Australia and worldwide who provided data about the use of PSMA in tens of thousands of patients and gave us the resources to be able to bring it to patients here in the United States. Thanks to everyone who brought PSMA to patients with prostate cancer. There is a lot of research going on to improve this and on other targets such as bone metastases and many others. The future is looking very bright.

Dr Nguyen: Fantastic. Well, thank you so much, Jerry and Andre, for this opportunity to speak with you, to learn from you, and to share your wisdom with our audience. Thank you to the audience for tuning in today. We hope it was useful for you, and we hope you will continue on to answer the questions that follow and complete the evaluation. Thanks, everybody, for tuning in.

This transcript has been edited for style and clarity.