Practical Applications and Clinical Utility of PYLARIFY® (piflufolastat F 18) Injection: An ¹⁸F-PSMA PET/CT Imaging Agent for Prostate Cancer

With commentaries by:

Neal D. Shore, MD, FACS
CMO, Surgical Oncology/Urology Genesis Care, US
Director, CPI, Carolina Urologic Research Center

Steven Rowe, MD, PhD
Associate Professor of Radiology and Radiological Science
Johns Hopkins University School of Medicine

A series of interviews was recently conducted with a panel of experts on prostate cancer imaging modalities that included Steven Rowe, MD, PhD, Associate Professor of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, and Neal D. Shore, MD, FACS, CMO, Surgical Oncology/Urology Genesis Care, US; Director, CPI, Carolina Urologic Research Center, Myrtle Beach, SC.

During these interviews, the experts shared their perspectives on innovation in the imaging of patients with prostate cancer and the identification of metastases. Topics covered included recent advances in prostate-specific membrane antigen (PSMA)-directed imaging, the advantages of positron emission tomography (PET) imaging, and the fusion of PET/CT or PET/MRI techniques. In addition, they also discussed the OSPREY and CONDOR clinical studies that led to the approval of PYLARIFY® (piflufolastat F 18) by the FDA in May 2021. The following is an edited transcript of the interviews. The videos can be viewed at http://tlg.site/upm-iwi.

Neal D. Shore, MD, FACS
CMO, Surgical Oncology/Urology, Genesis Care, US
Director, CPI, Carolina Urologic Research Center
Myrtle Beach, SC

Question: How do you see the role of PET imaging in the evaluation and management of men with prostate cancer?

Neal D. Shore, MD, FACS: As someone who has been diagnosing and managing patients with advanced genitourinary oncology challenges, and particularly for prostate cancer patients, I am absolutely thrilled that access to PSMA PET will bring US urologists, medical oncologists, radiation oncologists, and nuclear medicine radiologists to the forefront of diagnostic imaging, and thus more accurate staging.

Many of our colleagues around the world, particularly in Australia and Germany, as well as Latin America, Asia, and the Middle East, have had access to next-generation imaging PSMA PET technologies. PSMA PET imaging provides greater accuracy and understanding of the location of metastases that we could not previously detect with conventional imaging, such as CT scan and technetium bone scans.

Question: Are these technology platforms widely available? How aware are US urologists of these imaging modalities?

Neal D. Shore, MD, FACS: Conventional imaging, which we’ve had for several decades, has included technetium bone scan and multi-slice CT scan. These are good imaging technologies, but they don’t have the same level of detection of metastases, what we’ve historically thought of as microscopic metastases, and even perhaps oligometastases.

The beauty of newer-generation imaging PSMA PET technology is that we’re able to see these heretofore unseeable micrometastases. In the US, we’ve only recently had the ability and approval of the fluciclovine Axumin PET scan, and this has been advantageous and very helpful for many of our colleagues, especially for evaluating patients who have PSA or biochemical relapse. Also, this PET scan has been used to assess patients who have newly diagnosed, high-risk, localized disease. Unfortunately, we’ve been lagging in PSMA PET accessibility compared to our non-US colleagues. In December of 2020, we saw the approval of the PSMA Gallium 68 PET, but it was only approved in 2 institutions, UCLA and UCSF.

What I am extremely happy to share is that in May of 2021, the FDA approved the 18F-PyL PET PSMA technology, now known as PYLARIFY®.

Question: What do you think are the most important innovations in prostate cancer imaging in the last 5 years?

Neal D. Shore, MD, FACS: I think the most important innovation in imaging in prostate cancer in the last 5 years has been the improvement in MRI technology. And, most recently, the PET PSMA technology, which will undoubtedly provide state-of-the-art accuracy to detect metastatic disease.

Question: What is PSMA, and what is the role of this molecule in prostate gland physiology and biology? Why is it an important target for imaging tracers in prostate cancer?

Neal D. Shore, MD, FACS: Historically, we’ve had specific biomarkers in prostate cancer. Back in the day, we talked a lot about acid phosphatase, and we discovered prostate-specific antigen and now we have PSMA, prostate-specific membrane antigen.

It’s a bit of a misnomer because it’s not truly prostate-specific. We have PSMA expression in the kidneys. We have it in the salivary glands, and of course, we have it in prostate primary disease, organ of origin, and also in metastatic disease, and its expression appears upregulated with androgen deprivation therapy.

This is a transmembrane antigen. What’s particularly interesting about that concept is that there’s an intracellular and an extracellular component. The extracellular component (of PSMA) allows for us to “tag” it, for example with PYLARIFY®.

We can pick up where disease is (with PSMA PET). Ultimately, when we have therapeutics, we can target an antibody to the PSMA with a radioconjugate, which allows for the very novel development of theranostics as a standalone therapeutic.

Question: Could you clarify why PSMA PET/CT is part of the discussion when planning for optimal follow-up and longitudinal management of the prostate cancer patient after initial frontline therapy?

Neal D. Shore, MD, FACS: With initial frontline therapy, in which we traditionally use surgical removal of the prostate, prostatectomy, or some form of radiation therapy—intensity-modulated radiation therapy, image-guided radiation therapy, proton beam therapy, perhaps brachytherapy or combinations of external beam and brachy—we unfortunately don’t always cure the patient. We see this with the demonstration of PSA recurrence. When the levels are low, invariably, we don’t know where it’s coming from with conventional CT scan or technetium bone scan.

Even with the approval of the fluciclovine scan, we often are hard pressed to see identification of the disease on a micrometastatic level, even with PSAs between 0.2 and 1.0.

With the PSMA PET technology, we’re demonstrating much greater accuracy, with PSA values between 0.2 and 1.0, and assuredly, much greater accuracy with higher PSA levels.

The higher the PSA level, there’s a very nice correlation with extent of disease. It doesn’t just include soft tissue; it also includes location of bone and visceral metastases.

Question: How is PSMA PET imaging different from current conventional imaging that we use in staging of prostate cancer?

Neal D. Shore, MD, FACS: Conventional imaging has historically used multi-slice CT scan with or without contrast, and the resolution is always increased by the level of slicing. In other words, that’s 4-slice to 16 to 32, 64-slice technology, gives much greater resolution.

Technetium bone scan based upon using the technetium imaging agent has been challenging because of the many false positives that we see.

Lesions that show up in a technetium bone scan are not invariably consistent with metastasis, but they can be related to arthritic changes in bone, bone trauma, bone islands, bone cysts, or prior surgical interventions.

The excitement about having PSMA PET technology is it has a much greater degree of accuracy. Much greater so, regarding the findings of bone metastatic lesions, but also in helping us discern the presence of disease in soft tissue and visceral organs, classically the lung and liver.

Question: What are some of the advantages of PSMA imaging at the time of initial staging diagnosis in pre-frontline therapy, in terms of sensitivity, specificity, and clinical utility at large? What is the patient profile that would prompt you to consider ordering the PSMA PET in staging when you initially see a prostate cancer patient?

Neal D. Shore, MD, FACS: One of the challenges in diagnosing, staging, and evaluating a patient who is newly diagnosed with prostate cancer is, especially if their CT and technetium bone scan imaging assessments are negative, can there still be micrometastatic disease?

If micrometastatic disease is documented within the pelvis, or above the pelvis (aortic bifurcation) or within the retroperitoneum or perhaps within bone, as examples the symphysis pubis or the tuberosities, the ilium, or even more distant, the axial spine, then clearly our choice of therapy can be decidedly altered.

There might occasionally be supraclavicular lymph node metastases, or small pulmonary metastases that are hard to discern with conventional CT scans.

Interestingly, there may be some grade group 1, 2 patients who have certain germline variations, which could also predispose to micrometastatic disease that we would have never been able to detect with conventional imaging.

PSMA PET technology takes us to a whole other level, allowing us to discern whether the disease is confined to the prostate or is outside the prostate.

For all of us who treat prostate cancer—urologists, radiation oncologists, medical oncologists—we require the most accurate staging possible in order to best inform patients regarding their optimal treatment decision. If the staging is truly determined to be organ confined, we’re much more likely to either recommend a surgical extirpative alternative, such as prostatectomy or radiation of the entire prostate gland.

For radiation patients, if there is disease that appears to be within the pelvis, a radiation oncologist may give additional consideration to whole-field pelvic radiation.

If a scan shows the disease is above the pelvis into the retroperitoneum or vertebral spine that we didn’t see on conventional imaging, this could potentially significantly change the patient-physician shared decision-making discussion, potentially considering a systemic therapy.

Do we incorporate systemic therapies? Do we not proceed with localized treatment? These are very important considerations.

The answers are not completely nor perfectly elucidated, but this is going to provide us with much greater information to make more informed decisions and do the clinical trials to help us understand what stratification factors will make for the best decisions.

Question: Based on the fact that PYLARIFY® got a broad label, in the metastatic patient, why would PSMA PET be considered the preferred option, considering that you can also see metastasis and you know that the disease is M1? What is the added benefit of PSMA PET?

Neal D. Shore, MD, FACS: The added benefit of the PYLARIFY® PSMA PET for someone with metastatic disease versus conventional imaging has to be broken down into different groups. Does the patient have oligometastatic disease? This definition ranges from maybe 3 to 5 lesions, but is yet still debated.

Where are the lesions? Are they confined to the soft tissue of the pelvis? Are they in the retroperitoneum? Is it a mix of 1, 2, or 3 bone areas and/or nearby soft tissue? Or are there very far away areas of concern, supraclavicular, or in the skull? Are they in the sternum? Are there pulmonary metastases?

This technology is important because it’ll tell us that we have many different options for our patients with metastatic castration-sensitive prostate cancer.

Findings have varied based upon the trial evidence of low- versus high-volume disease, as well as the location of the disease in addition to a patient’s history of comorbidities and other factors such as the tumor differentiation.

The PYLARIFY® PSMA PET is going to allow for a more informed decision between patient and physician.

Question: What are some of the theoretical or clinical limitations of PSMA PET, such as false positives? What are some of the practical limitations, as far as patient access, universal availability, etc?

Neal D. Shore, MD, FACS: Accessibility for PSMA PET, what some would call next-generation imaging, is key.

Part of accessibility is making sure that any new technology is affordable, whether it’s a biomarker, a new imaging technology, or a new therapeutic. It’s one thing for a regulatory agency to approve it, but you also have to have a way forward to provide both reimbursement and logistical accessibility.

There are some sophisticated methodologies that come into play to create the 18 F PYL imaging agent. It involves having access to a cyclotron. Then, from the cyclotron, once the assay is prepared and processed there has to be a transportation supply chain developed.

I’m very confident that the manufacturers of PYLARIFY® have given this great thought, and at least in the US, we’re lucky in that we have typically surmounted supply chain issues.

Especially outside of the traditional tertiary high-volume centers, many smaller hospital systems in suburban and rural areas will now have greater access to PYLARIFY. There’s a long half-life associated with the 18 F PYL agent (t1/2 = 109.8 minutes), which provides more time for transportation once you have processed the imaging agent.

Question: Is PSMA PET imaging effective across all degrees of PSA level elevation? You commented specifically about the patient who has really low, yet detectable, PSA levels – what is the value of PSMA PET in this population?

Neal D. Shore, MD, FACS: What we’ve seen historically is, when we think back to conventional imaging, we have really not been able to discern soft tissue lymph node positivity, unless the node was ≥1 cm.

Likewise, I mentioned earlier the lack of accuracy often with technetium bone scan regarding its positive findings, because of the differential diagnosis of lesions being not just consistent with metastatic prostate, but they could be bone cysts, trauma, degenerative joint disease.

What we see with the PSMA PET, and particularly some very nice work that’s been done in 2 excellent trials known as the CONDOR and OSPREY, whereby the trials demonstrated correlative improvement in detection of disease location with relatively low PSA increases.

For patients who have a PSA of ≥5, there’s a >90% detection and agreed upon localization of that disease by independent readers. That speaks to the importance of our radiology colleagues being able to interpret tests correctly, particularly our nuclear medicine radiologists.

For PSAs between 2 and 5, we see a detection of disease in upwards of 65% of patients who have a biochemical relapse. For PSAs between 1 and 2, likewise, we see upwards of 50% of patients with demonstrable disease.

For patients with PSAs between 0.4 and 1.0, we also see demonstration of metastases in just slightly <50% of the patients. For patients with PSAs demonstrable—not undetectable, but on some level—upwards of 40% of patients will have evidence of where the disease is located, previously not detected with conventional imaging. This is a really important change, in other words, it’s a game changer, essentially replacing conventional imaging.

Question: We have heard this term, especially nowadays, that we can pick up this disease, oligometastatic disease. Can you define oligometastatic disease? What is the potential role of PSMA PET in identifying these patients that may be candidates for metastatic therapies? What are these metastatic therapies, and why are they important in the treatment for oligometastatic disease?

Neal D. Shore, MD, FACS: It’s controversial as the definition of oligometastatic disease is controversial. Oligo, from the Greek word “few” has different interpretations, and I’ve read papers and studies done where it’s been defined as low as 2 or 3 lesions and upwards of as many as 5 lesions. These lesions may not be discerned through conventional imaging.

Now, why does it make a difference? Well, if you have isolated lesions that you cannot visualize on a CT scan, and you don’t have access to PSMA PET, or that your technetium bone scan is negative, you could make an argument to do focal stereotactic body radiation therapy or potentially robotic or laparoscopic removal of PSMA PET positive lymph node. Importantly, we’re conducting additional trials to better appreciate optimal strategies for these patients.

As opposed to starting the patient who’s got a rising PSA and a PSMA PET positive lymph node(s) on testosterone suppression, and that same patient with the rising PSA with a CT and Tc Bone scans which are read as completely normal, and yet the PYLARIFY® PSMA PET showed a confluence of small nodes in or an isolated bone lesion, then a clinician could potentially offer the patient local node removal, or one could potentially consider focal radiation. You can certainly make those considerations, and these are the trials that really need to be done for us to better understand optimal treatment decisions.

Question: Many practices have been using multiparametric or mpMRI, high-definition MRI for the last few years. Some practices are very loyal to it. How has mpMRI evolved as a tool for imaging in prostate cancer? How would you juxtapose that now that PSMA PET scans are available? Obviously, there are 2 schools of thought there, as you know very well.

Neal D. Shore, MD, FACS: Multiparametric MRI is important for deciding when to biopsy or certainly to do a repeat biopsy, and there’s some controversy there, but it clearly has a role.

It’s in the guidelines in Europe for initial biopsy and repeat biopsy. In the US, it’s only in our guidelines for consideration of repeat biopsy if there is a significant PI RADS finding.

For patients who have documented prostate cancer, whether they’re undergoing a surgical removal or radiation treatment planning, mpMRI can further inform the surgeon or the radiation oncologist for potential fields of exploration specifically for treatment, potentially for nerve sparing, and even for other aspects of surgical dissection.

Complementing the mpMRI with the markedly improved accuracy of PET PSMA technology can further augment that understanding of how far you would place your field of radiation or where you would aim your surgical dissection. It may also improve or extend your pelvic node dissection for surgeons and, again, also enhance your field for pelvic radiation.

Question: What are the patient characteristics, from the point of view of PSA, grade, or risk stratification, that the community urologist should consider when referring a patient for a PSMA PET scan if they suspect metastasis in patients who are undergoing initial definitive frontline therapy?

Neal D. Shore, MD, FACS: When we diagnose patients who we believe historically to have clinically localized disease, we know that a patient with a normal digital rectal exam and a PSA of <10 who has grade group 1 or 2 disease on biopsy is highly unlikely to have micrometastatic disease and highly unlikely to have locally advanced disease.

So much so that for most of these patients we recommend the strategy of active surveillance. There always are exceptions. There may be an exception if the patient has a high volume of grade group 2 disease, lots of Gleason 6, longer millimeter core length or percentage core involvement.

It may be a patient who has a borderline PSA elevation that’s 9.9. It may be a patient within that same grade group 2 who has a significant family history of cancer, but yet either did or did not undergo germline testing. Maybe they have a homologous recombinant repair gene alteration, as example, BRCA2.

These patients might benefit from a PYLARIFY® PSMA PET, because you might be thinking, “I really wanted to do active surveillance, but maybe it does look to be the case that the disease is more extensive than I thought it to be, either locally or within pelvic nodes.”

For our grade group 3, 4, and 5 patients—the 4+3s, the 4+4s, the 4+5s, and 5+5s—these patients are agreed upon to harbor clinically significant cancers. Over the course of time, whether we do prostatectomy or radiation, and depending upon their histopathologic risk, there can be failure rates of 15% to 50% with an active intervention.

How can we better stage those patients? In all of those patients, the grade groups 3, 4, and 5, regardless of their family history, and almost invariably, regardless of their PSAs, but, of course, even more so, the higher their PSA, and more so if they have palpably abnormal digital rectal examinations, they’ll benefit from a PYLARIFY® PSMA PET.

The staging could have a clear implication as to whether a patient would proceed to surgery, radiation, or potentially one or the other with combination systemic therapy.

The systemic therapy may or may not include only testosterone suppression, but it could also include some of the more novel combination strategies that we already have in metastatic castration-sensitive prostate cancer.

Certainly, these are going to be considerations that are going to weigh heavily as we start to stratify patients in clinical trials. Those who are getting next-generation imaging—in other words, PSMA PET—versus those who are just making decisions by their information from conventional imaging.

Question: What are the patient characteristics that the community urologist should consider when thinking about ordering a PSMA PET scan in biochemical recurrent patients?

Neal D. Shore, MD, FACS: For those patients who do undergo an active interventional treatment, such as surgery or radiation, and then they fail with detectable PSA of any level after prostatectomy or a rising PSA after a nadir, right now classically the ASTRO/Phoenix definition, I think that’s going to change dramatically as we move forward.

That definition for failure was largely based on conventional imaging. When we see biochemical recurrence or PSA relapse, this is going to be a really interesting era of imaging as we now have more advanced technologies to tell us exactly where that PSA is emanating from. What is the source of the PSA? In the case of a radiation failure, is it just within the bed of the prostate or extra prostatic?

My review of the current contemporaneous literature suggests that a PSMA PET, and now with the approval of PYLARIFY® in the US, is the best technology to help you understand where the disease is coming from for the PSA recurrence.

The challenge that we have is what to do with that information. How do we treat these patients? Do we initiate testosterone suppression? Intermittent? Continuous? What are our triggers? Is it based upon the doubling time still? Is it based upon histopathology, time from relapse from the active treatment? These are still important study questions.

Question: Which algorithms can one use in the clinic to identify patients who are at higher risk of prostate cancer spreading to pelvic lymph nodes and beyond? Who would need to be referred for PSMA scan?

Neal D. Shore, MD, FACS: Anybody, historically, who has a PSA of >10 with a Gleason 7 or higher, through AUA guidelines, has been recommended for getting full CT body imaging as well as technetium bone scan.

Given the sensitivity of PSMA PET and the data that I’ve seen from CONDOR, my recommendation would probably be to consider PSA levels lower than that. Clearly, for patients who have Gleason 8, grade group 4, grade group 5, if they have even low PSAs and even a fairly unimpressive digital rectal exam, I think I’ll be getting a PSMA PET on all of those patients.

High-risk patients and very high-risk patients, the grade groups 4s and 5s, are invariably those patients who we worry about having micrometastatic disease that we were never able to pick up previously on conventional imaging.

Additionally, the grade groups 3s, the grade group 2s that are enriched and/or have family histories of concern, my threshold for ordering a PYLARIFY® PSMA PET will be that much lower in comparison to traditional conventional imaging.

Question: What are your thoughts on the recent updates to the NCCN Guidelines around the use of PSMA agents for patients with prostate cancer/PYLARIFY?

Neal D. Shore, MD, FACS: The recent NCCN Guidelines recommendations for PSMA PET (18F PYL and Ga 68)3 corroborates the Society of Nuclear Medicine & Molecular Imaging (SNMMI) guidance for PSMA PET utilization;4 this clearly heralds the “game changing” consideration for the greater accuracy of PSMA PET in comparison to our historical imaging capabilities.

Steven Rowe, MD, PhD
Associate Professor of Radiology and Radiological Science
Johns Hopkins University School of Medicine
Baltimore, MD

Question: What is F 18 DCFPyL?

Steven Rowe, MD, PhD: F 18 DCFPyL or sometimes, in the vernacular, just PyL, is a small organic molecule radiotracer. One end of the molecule is based around a urea moiety that is a very high affinity binding moiety for the active site of PSMA.

Then, there’s a linker from that urea moiety to another moiety that contains the F 18 or radio fluorine, the radionuclide that allows us to create images. So, one part of the molecule is what actualizes binding to PSMA and as a result prostate cancer, then there is a linker, and the other end of the molecule allows us to create PET images.

Question: There have been many key features and findings from the clinical trials supporting PyL’s clinical development to date, primarily the OSPREY and CONDOR studies. What are some of the key features and overall top findings of the OSPREY and CONDOR studies for PyL?

Steven Rowe, MD, PhD: There are 2 key trials that have really laid the groundwork for the recent approval of PYLARIFY®, and those are the OSPREY clinical trial and the CONDOR clinical trial.

OSPREY was the more complicated of the 2 trials. It had 2 cohorts in it. One of those cohorts was composed of men with newly diagnosed NCCN high-risk prostate cancer.

Here, conventional imaging was typically CT abdomen and pelvis and bone scan. Although some men had pelvic MRI instead of the CT abdomen and pelvis, for the most part, men were imaged with CT and bone scan.

In the first of those cohorts, the men with high-risk prostate cancer, after imaging they went on to a prostatectomy with an extended pelvic lymph node dissection. The goal of this cohort was to show the sensitivity and specificity as well as positive predictive value and negative predictive value of PyL in the context of nodal staging in primary disease. Because these were men with high-risk cancer, they had some risk of having nodal involvement.

Among the first cohort of men, those with high-risk prostate cancer, the radiotracer was found to have a relatively modest sensitivity in the 40% range but an exceedingly high specificity that was close to 100%. While very small-volume nodal disease might be missed by the scan, if there was abnormal uptake in the node, you can be fairly assured that that was true positive disease.

CONDOR was a somewhat simpler study that included men who had previously been treated with curative intent for prostate cancer and now had rising PSAs. The goal was to image those men, and then have various correlates to be able to figure out if their imaging findings were true positive.

Often, these lesions couldn’t be biopsied. They were too small. They were too subtle on conventional imaging. Although they could be biopsied, that was a potential standard of truth in the trial.

There are other standards of true positive such as confirmation with another FDA-approved radiotracer, confirmation with change over time on conventional imaging within the study window, or treatment with radiation to ≥1 sites of disease without systemic therapy.

Overall, CONDOR found that the detection efficiency of the scans or seeing anything on the scan increased with PSA. That was expected. We’ve seen that in various other studies with PSMA-targeted radiotracers.

What was called the correct localization rate in the trial, very similar to positive predictive value, was very high across PSA levels. Even among patients with very low PSA levels, even though often the scan wouldn’t necessarily show anything, if it did show something, it was typically showing what was a true lesion.

Question: For patients with high-risk prostate cancer, either biochemical recurrence or later on, with rising PSA, what scanning technique according to the literature and your own expertise performed better with regard to sensitivity and specificity? Is it mpMRI or PyL, and why do you think that difference exists?

Steven Rowe, MD, PhD: In men with biochemical recurrence, or recurrence overall of prostate cancer, and getting into oligometastatic disease, conventional imaging including mpMRI has played an important role in trying to identify those men who have a local recurrence and might benefit from salvage radiation. Men who might have more widespread disease and weren’t going to benefit from a salvage therapy and might need systemic therapy. What PyL and other PET radiotracers that have entered the prostate cancer realm give us is a chance for a broader systemic staging.

We typically are going to image from around the eyes. Skull base down to the mid thigh. You’ll sometimes hear that as “eyes to thighs,” but skull base to mid thigh is a typical field of view for a PET scan.

For men who do have disease outside of the prostate bed after a prostatectomy, and in whom it would likely be futile to do salvage radiation alone, we can identify those men with higher sensitivity and with higher accuracy and perhaps more confidence with some of the new PET radiotracers. PyL and the other PSMA radiotracers are the highest sensitivity agents that we have right now.

Question: There are other PSMA-targeted tracers, specifically 68Ga. What are the key differences from an imaging diagnostic performance perspective between Gallium 68 PSMA-targeted tracers and PyL, and more specifically, with regard to spatial resolution and false negative rates?

Steven Rowe, MD, PhD: There are now 2 FDA-approved PET radiotracers that target PSMA. One of those has a limited approval at a couple of sites in California, and that’s Gallium 68 PSMA 11. The other is PyL.

Between those 2 radiotracers, just about everyone would say that their sensitivity, particularly in recurrent patients with low PSA levels, is better than anything that we’ve had before, but there are differences.

PyL has a relatively longer half-life, but more importantly, it has a higher positron yield. Essentially, all the decays that come from PyL are positrons, and it has a relatively low positron energy. The positrons don’t move very far through tissue before finding an electron and annihilating. The annihilations occur closer to where the radionuclide was localized.

The contrast resolution is higher, and the spatial resolution is higher. Those 2 things likely combined to help pick out very subtle lesions that may be important to, say, a patient with low PSA who’s having a biochemical recurrence.

Head-to-head comparisons have been relatively limited between these. It’s difficult to necessarily power a head-to-head study to some clinically meaningful outcome because both radiotracers are, in all honesty, very good.

I don’t know that we’re going to see that definitive prospective multi-hundred patient clinical trial that compares them.

Question: Another biochemically targeted tracer that has been quite widely used in men with advanced prostate cancer, at least biochemically recurrent cancer for staging, is Axumin® (fluciclovine 18). What are some of the potential advantages, because they’re both F 18 based, between F 18 PyL versus F 18 fluciclovine?

Steven Rowe, MD, PhD: There are 2 FDA-approved F 18-labeled radiotracers for prostate cancer. One of them has been in use for a few years now. That’s F 18 fluciclovine or Axumin®. Now, there is F 18 DCFPyL or PYLARIFY®. Both of these are F 18 labeled. They both have the intrinsic advantages of F 18 in terms of being able to be mass produced and transported to many parts of the country.

However, the PSMA-targeted radiotracers in general and PyL perhaps in particular do seem to have advantages in certain clinical contexts relative to Axumin®. The head-to-head data between PSMA agents and Axumin® tend to be with the Gallium PSMA 11 agent and Axumin®.

Question: How well did the PyL tracer perform with regard to overall sensitivity and positive predictive value in the PyL clinical trial program both for OSPREY and for CONDOR?

Steven Rowe, MD, PhD: Common performance metrics for radiotracers would include sensitivity for being able to identify a potential site of disease and then positive predictive value. If there’s uptake of a radiotracer in a given location, how commonly does that turn out to be a true positive site of disease?

In terms of sensitivity, in the OSPREY trial in high-risk preprostatectomy patients, the sensitivity end point actually wasn’t met for that trial. That was 1 of the primary end points.

Men with high-risk preprostatectomy disease can still benefit from a radiotracer in that you can potentially identify those men who do have disease outside of the pelvis that may not be cured by surgery or may not be appropriate for surgery in some instances. You can also be assured that if there is uptake on the scan in nodes, those represent true positive sites of disease. As a surgeon, if one has to pick a side to be a little bit more aggressive in terms of a pelvic lymph node dissection, the scan may provide some information along those lines.

Sensitivity in a biochemical recurrence cohort does seem to be a little bit...I don’t know if I want to say better. It is a little context dependent, but it does seem to be a little bit more robust perhaps than in the preprostatectomy patients. Although correlated to PSA, it runs anywhere from 30% to 50% at very low PSA levels, but approaches 90+% at PSAs that are a little bit higher.

The positive predictive values were excellent across the board. Whether they were in lymph nodes, bone, or other soft tissue sites of disease, there were great positive predictive values across the board. In that metastatic setting, maybe a patient’s being worked up for oligometastatic disease or has a relatively limited volume of disease, so anything that you see that lights up is generally going to be a positive site of disease.

The one caveat to that I would say is that there are pitfalls. There are known structures and known normal variants that have PSMA uptake. It’s important for both interpreting physicians as well as referring physicians to be aware of those pitfalls. The positive predictive value is maximized in the context of understanding those pitfalls and not being a victim of those pitfalls in overhauling disease.

Question: What are your thoughts on the availability of PyL in regular clinical care rather than the clinical research setting? How do you see this dynamic evolving in the future in US urology and medical oncology practices?

Steven Rowe, MD, PhD: With the FDA approval of PyL we’re going to see a relatively rapid adoption of this agent. That was the experience with Axumin®.

Once there was something available that was better than conventional imaging, people flocked to it. Some of that’s driven by patient preference. Patients want to know where their disease is. Some of it is driven by clinician preference. You don’t necessarily want to be shooting in the dark.

I think that there is going to be a relatively rapid uptake of PyL. It is going to be interesting to see how this evolves over time. We’ve so far mostly seen it used in the very carefully controlled setting of clinical trials, even at those places that may have been working with this agent for several years now.

Typically, that was on protocol. Patients had to meet inclusion and exclusion criteria. We’re going to be getting away from that. The use of the agent is going to become a bit more individualized, a bit more dependent upon referral patterns.

It will be important for us to continue to prospectively design trials to capture clinical data and answer the clinical questions that we may not have yet. It will also be important to be retrospectively gathering data and to have programs to ensure that we’re capturing all the information from the men that we’re imaging with this agent in the interest of continuing to drive the science, drive what we know about its use and how to maximize the use of this agent.

Again, to some extent, the horse has left the barn. With the approval, we’re going to see use in many contexts that we had not designed clinical trials for, but it is important to continue to collect that data to make sure that we’re using it right, and that we eventually can leverage the maximum amount of information out of how to use this.

Question: In order to actually give the radiotracer to the patient, you need to have an optimal infrastructure, including a production and distribution network. How would you envisage this optimal infrastructure now that PyL is available? How is this optimally delivered exactly where the product is needed at the point of care in the clinic and in the hospital where prostate cancer patients are seen?

Steven Rowe, MD, PhD: One of the advantages that we’re now going to have with an F 18-labeled PSMA agent is that because there has been such widespread use of F 18 fluorodeoxyglucose (FDG) in oncology for a number of years, as well as the adoption of other F 18-labeled radiotracers, there is a huge production bandwidth to make F 18-labeled radiotracers. There are industrial cyclotrons all over the US, Europe, Australia, and many other parts of the world that are able to make F 18-labeled radiotracers.

As things get up and running, and as all these industrial cyclotrons begin churning out DCFPyl, the distribution networks to get it to the places that can utilize it already exist. That’s a major strength. It means that there’s not a lot of money or infrastructure that necessarily needs to go into building those networks.

Another nice thing about DCFPyL in terms of already existing workflows is there are a couple of common time points that people may image post-injection of the agent.

For many places, 1 hour fits in perfectly with how we already image FDG. FDG is typically injected and then an hour later, the patient gets imaged. We already have all of our workflows optimized for a 1-hour uptake time post-injection.

At least in our PET center, there has been very little adjustment necessary to fit DCFPyL into the workflow. If everything falls into place, there should be plenty of doses available. Once that happens, technologists are already very familiar with how to inject the patient, how to wait the proper amount of time, get them on the scanner, and get the scan done. There is already a robust framework that exists to have DCFPyL widely available.

Question: What are your thoughts on the recent updates to the SNMMI guidelines on appropriate use criteria for PSMA PET imaging?4

Steven Rowe, MD, PhD: The appropriate use criteria recently published by the SNMMI is an important step forward for PSMA PET. Contributors to the criteria included both imaging experts and clinicians from across the spectrum of providers who treat men with prostate cancer. The document will serve as a touchstone for insurance companies who will be deciding what indications to cover for PSMA PET. It is also a living document that will evolve rapidly in coming years, particularly as PSMA-targeted therapeutics gain regulatory approval in the United States.

References

  1. Morris MJ, Rowe SP, Gorin MA, et al. Diagnostic performance of 18F-DCFPyL-PET/CT in men with biochemically recurrent prostate cancer: results from the CONDOR phase III, multicenter study. Clin Cancer Res. 2021;27:3674-3683.
  2. Pienta KJ, Gorin MA, Rowe SP, et al. A phase 2/3 prospective multicenter study of the diagnostic accuracy of prostate specific membrane antigen PET/CT with 18F-DCFPyL in prostate cancer patients (OSPREY). J Urol. 2021;206:52-61.
  3. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN Guidelines®) prostate cancer, version 1.2022 – September 10, 2021. www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed October 6, 2021.
  4. Society of Nuclear Medicine & Molecular Imaging. Appropriate use criteria for prostate-specific membrane antigen PET imaging. https://s3.amazonaws.com/rdcms-snmmi/files/production/public/FileDownloads/AUC/PSMA%20AUC%202021Sep09_Final.pdf. Accessed October 6, 2021.

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