PYLARIFY®, F 18-labeled PSMA Targeted PET Gains US FDA Approval - Michael Morris

May 28, 2021

Michael Morris, MD joins Charles Ryan, MD in a discussion on the United States (US) FDA Approval of PYLARIFY®, an F 18-labeled prostate-specific membrane antigen (PSMA) targeted positron emission tomography (PET) imaging agent. The F 18 tracer went through two qualifying clinical trials the CONDOR trial and then OSPREY trial. This is the first time a national commercial approval will render PSMA imaging available across the US.


Michael Morris, MD, Medical Oncologist Clinical Director, Genitourinary Medical Oncology Service & Prostate Cancer Section Head, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Charles J. Ryan, MD, the President and Chief Executive Officer of The Prostate Cancer Foundation (PCF), the world’s leading philanthropic organization dedicated to funding life-saving prostate cancer research. Charles J. Ryan is an internationally recognized genitourinary (GU) oncologist with expertise in the biology and treatment of advanced prostate cancer. Dr. Ryan joined the PCF from the University of Minnesota, Minneapolis, where he served as Director of the Hematology, Oncology, and Transplantation Division in the Department of Medicine. He also served as Associate Director for Clinical Research in the Masonic Cancer Center and held the B.J. Kennedy Chair in Clinical Medical Oncology.

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Charles Ryan: Hi, Chuck Ryan here from the University of Minnesota. Joining me today is Dr. Michael Morris, a Medical Oncologist and a Professor at Weill Cornell and Prostate Cancer Section Head and full member at Memorial Sloan Kettering Cancer Center in New York City. Dr. Morris is one of the lead investigators on the DCFPyL data that has just been released and led to the regulatory approval of this new PSMA-based imaging agent from Lantheus. Mike, tell us a little bit about this new agent and how it works.

Michael Morris: Sure thing. So DCFPyL is a small molecule that targets with high affinity, Prostate Specific Membrane Antigen or PSMA, which is expressed on most prostate cancers, regardless of distribution of disease. It's an F-18 labeled tracer and it's gone through two qualifying clinical trials. One termed CONDOR, and one termed OSPREY, which looked primarily at the high-risk preoperative population. In OSPREY in its first cohort metastatic disease and relapsed disease in its second cohort. And in the CONDOR trial at the biochemically relapsed population after primary therapy. So today's FDA approval for PyL is the first time really that we have a national commercial approval that will render PSMA imaging available pretty much to patients across the country on a pretty accessible context. That is with an F-18 radiolabeled tracer.

Charles Ryan: So this is very different from Gallium-68 PSMA that has already been approved. The standard PSMA PET Scan that we've talked about or the PSMA PET Scan that has been discussed before. This is [crosstalk 00:02:04].

Michael Morris: It's interesting that you ask that Chuck. Just to clarify from a technical standpoint, although the Gallium-68 is a different tracer than the F-18, the behavior of these two in terms of their performance characteristics are quite similar. But as it stands today, their regulatory status is quite different. So as you alluded to Gallium-68 right now is approved at UCSF and UCLA. The PyL approval, however, is on a national basis. We do anticipate that that will change pretty shortly and there will be a national commercial FDA approval for Gallium-68 coming up sometime in the next couple of months. So that's anticipated, which will really put two very, very good tracers into the marketplace for patients to access.

Charles Ryan: So I want to clarify a couple of things. So this is different from the Gallium-68 because of the accessibility and the ease perhaps with which Fluorine-18 can be transported and produced, correct?

Michael Morris: Yeah. That's true from a logistical standpoint, F-18 has wide distribution because F-18 is used in FDG PET. So already, those networks are in place to produce and synthesize ship and deliver tracer across the country. Gallium-68 needs to be made onsite at it with a generator, so that's more available to large radiology centers or cancer centers, et cetera. So there is a difference in terms of logistics and ease of use. And I think that that will probably determine who gets, which tracer as opposed to there being significant differences in terms of performance characteristics.

Charles Ryan: So there's not a clinical reason to choose one over the other at present?

Michael Morris: No, there really isn't. They're both excellent tracers and they have very, very similar properties.

Charles Ryan: Okay, very, very-

Michael Morris: They're both far superior to what the alternative is.

Charles Ryan: Let's talk a little bit about what we have as an alternative. We have obviously standard imaging Axumin PET Scans, et cetera. Given the indication here for PyL, how does this differ? What does this do for us clinically?

Michael Morris: So PyL and other PSMA PET tracers can detect disease far bit earlier and with greater accuracy than cross-sectional imaging or with bone scintigraphy. For either cross-sectional imaging or bone scintigraphy, you're essentially waiting for anatomic abnormalities to declare the presence of cancer, either an enlargement of adenopathy or the presence of abnormalities in a visceral organ or for bone scintigraphy abnormalities in the surrounding bone, which is not really tumor imaging specifically at all.

Whereas, PSMA PET imaging is really directly targeting the cancer itself. You don't need to wait until a lesion is big enough to see it in cross-sectional imaging or identify it as abnormal. So it is a much better way to detect early disease and much more accurately stage a patient or declare a relapsed patient, their sites of disease, whether those may be local within the prostate bed or intact prostate, or local regional in the pelvis or distant in the rest of the body. So it gives you both a real, lead time in terms of making treatment decisions based on an accurate description of the patient's distribution of disease, and as well if you can do so early. So it's early identification and accurate identification.

Charles Ryan: The results from the CONDOR and the OSPREY studies which have been covered elsewhere really showed that these results can help us to intensify a therapy or de-intensify a therapy based on the positivity or the negativity of the scan which is really I think one of the key clinical deliverables of this more sensitive scan.

Michael Morris: Absolutely. If you look at CONDOR, in which all of those patients in CONDOR had negative imaging studies, negative standard imaging studies. So there was no information for any patient who is eligible for assessment in CONDOR. 60% of the treatment plans essentially were changed as a result of having the PSMA PET. Now what's nice about this label is that it does not require you to perform standard imaging before ordering a PSMA PET. That's a nice change from previous labels of molecular imaging and prostate cancer because it really does seem like a waste of resources to order an inferior study in order to order a superior study.

Charles Ryan: Right, so we probably won't run into situations with payers where they demand a negative standard study before we are able to order this. In fact, this could be cost-effective in that regard.

Michael Morris: Not if it were intelligent and rational decision-making. There are some circumstances still where payers demand that you have a negative inferior scan in order to order the superior scan. But certainly from a labeling standpoint, the fact that the agency has recognized that PyL is superior to standard scans and can be substituted for those. There may be circumstances where you do want to add a value added standard scan. So for example, in a post prostatectomy patient, if you want a good understanding of the anatomy now of the prostate bed, which a PET CT doesn't necessarily afford, there's a rationale for that. But you don't have to get a bone scan, for example, in order to order a PyL PSMA scan.

Charles Ryan: So we could and we probably will spend many conversations over the next few years further clarifying what the results of these scans enable us to do for our patients. Not only that, but how that impacts patient outcomes. I think it's really key to speak to that a little bit. What you talked about critically was it changed the clinician's perspective on intensifying or deintensifying the therapy. But in terms of the long-term outcomes, we still have a lot of work to do in that regard. Are there going to be opportunities for studying that, like radiating isolated tasks? These are the things we talk about a lot currently in managing recurrent disease.

Michael Morris: Absolutely. Anytime we introduce better technology for more accurately identifying sites of disease, it's going to open the door to a multitude of questions of what to do with that information and how to turn that information into optimized treatment paradigms. So there are many opportunities and many trials that are already going that are beginning to accrue based on PSMA imaging in order to not only see what's an actionable finding, but then when you identify what an actionable finding is, what's the optimal thing to do about it? Is that combination of therapy? Is that just focal therapy? How do you yield the best outcome from the information delivered to you with a treatment paradigm that you test on a clinical trial? That's really... I think the next five years worth of work, which is figuring out what's the biomarker that's delivered and what to do about it.

Charles Ryan: Right, right. It's a great example of a new technology opening up all kinds of questions that we now have to go out and answer and it's going to be interesting to watch that field. I look forward to seeing you lead it. These PSMA imaging data come out at the very same time, virtually as PSMA-based therapies, data are coming up from the VISION trial. You were a key member of a large team of people running the VISION trial. Speak to us about the integration of PyL and PSMA imaging, generally with PSMA-based radioligand therapy.

Michael Morris: Sure, just to clarify. There's really three leaders of the VISION trial. I just want to make sure everybody gets their due credit. In the US PI of the study is Oliver Sartor, he's European PI as well. And I was the Chair of the Scientific Committee.

So I think that the real opportunity that PSMA imaging opens up from the standpoint of treatment is that it identifies patients who have PSMA expressing tumors. That really opens the doorway to a radioligand therapy where you'd follow the PSMA Scan with a radioligand sufficient to kill prostate cancer cells as a payload. The VISION trial used that approach. That's a Phase 3 study that looked for really advanced prostate cancer at really advanced prostate cancer patients. Post-abiraterone and enzalutamide, post-chemotherapy as well, and then randomize them to a non-chemotherapeutic standard of care plus or minus Lutetium-177 PSMA-617.

Now, the eligibility requirement was that patients have a PSMA-positive PET Scan in order to go on to the study. And as we know, from a previous press release, that study is positive both for radiographic progression-free survival and for overall survival. So this is the first demonstration of how PSMA PET can be used as an eligibility criterion as the first of two steps. The second of which leads to life-prolonging PSMA-directed therapy. So the details of that data will be available very shortly. And I think that that probably is it's own discussion in terms of reviewing those details, but suffice it to say that with the approval of PSMA PET on a national level, you can now deploy radioligand therapy on a national level without worrying, "Hey, where are the patients going to get a PSMA Scan from?"

Charles Ryan: That's a key point and a really big advance. We don't yet know what the role of the PSMA-based imaging is response to therapy. It's really about identifying patients for PSMA-based therapy, correct?

Michael Morris: Yeah.

Charles Ryan: So we'll be doing [inaudible 00:12:54] serial PyL scans on patients as an outcome measure.

Michael Morris: I think that we can't get ahead of our skis in terms of where the data are. So using PSMA scans as an indicator of a favorable treatment response, other than identifying that you've hit the target with your therapy is something that we still have to explore, just like we did with bone scintigraphy, in Prostate Cancer Working Group 3, prospectively examining in multiple trials, the relationship between progression on a bone scan with overall survival. We still have to look at the changes in a serial PET... PSMA PET CT, and see what the clinical meaning or import is.

There are pluses and there are minuses in that. The pluses, it's your only way of really directly [inaudible 00:13:48] the cancer as a reflection of anti-tumor effects from an imaging standpoint, so you're really seeing what the therapy is doing to the cancer. But the downside is we know that other indicators of direct anti-cancer therapy like PSA have not panned out to be closely associated with overall survival. And this Light PSA is an early indicator, as opposed to a bone scan which is a very late indicator of a treatment failure or potentially of a treatment benefit. So there's much to learn about how to use this in series, looking at it as a reflection of a treatment effect.

Charles Ryan: Right. You've just outlined... I think over five years of research or more that will take place with dozens, if not more than that, of clinical researchers and probably thousands of patients. So this is a great example of an important research, finding a new regulatory pool that's really going to open up, I think, a whole new area of research across the world in terms of how we assess prostate cancer patients over time.

Thank you for all of this insight. And Michael, I want to congratulate you and your team for this great work that led to this regulatory approval and look forward to hearing more from you as time goes on.

Michael Morris: Oh, thanks so much, Chuck. I just want to make sure that we recognize that project like this really is a multidisciplinary, multi-institutional and ultimately multinational effort. I think we have to recognize that PyL originated in Martin Pomper's lab at Johns Hopkins. The Hopkins group did a terrific job developing it in its early phase studies and then as it went to Phase 3, there's really was a combined effort on the part of urologists, medical oncologists, radiation oncologists, interventional radiologists, nuclear medicine physicians, and really it was quite a multidisciplinary effort. Well, we can't ignore the fact that it emanated out of a collaboration between academia and industry, now Lantheus, but previously it was Progenics. So with all of these disciplines, institutions, expertise, academics, industry experts, it really was the kind of thing that could yield this such important product for patient care.

Charles Ryan: The outstanding point is it's actually is a very unique study in that regard and the multidisciplinary nature of all of it. So Michael Morris, Prostate Cancer Section Head at Memorial Sloan Kettering Cancer Center, thank you for your time and congratulations again.

Michael Morris: Thank you very much, Chuck. Thanks for having me and for letting everybody know what's going on on new findings today in the world of prostate cancer.