Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today, a friend and colleague, Dr. Chuck Ryan, who is the Director of Hematology, Oncology, and Transplantation, as well as being a GU medical oncologist at the University of Minnesota. Thank you so much for speaking with me today, Chuck.

Charles Ryan: Happy to be here.

Alicia Morgans: Wonderful. So I wanted to talk with you a little bit about the rollercoaster that was 2020, not related to the biggest issues that we've dealt with in terms of COVID and the effects that our patients and practices and all of that, but really on some therapeutic imaging and other advances that I think really deserve attention and a recap as the year is winding down. So let's start by talking about sort of targeted therapies, things like PARP inhibitors, and what are your thoughts on these two new approvals and the studies that led to them?

Charles Ryan: Right, so despite COVID, there was actually a lot of progress for men with prostate cancer this year. We had some trials that matured and new drugs that were approved. And it's really exciting to be able to talk to you about this as we end this year. And I think that perhaps we can even think about ending 2020 on a high note, in particular when we talk about prostate cancer patients. So PARP inhibitors, although these are not an entirely new therapeutic class, 2020 was the year that two of them were approved for prostate cancer. The first one is olaparib, and the second one is rucaparib and they have very similar mechanisms of action. Slightly different approvals based on study design, as opposed to different sort of spectrum efficacy. Olaparib is the one that's admittedly further along because it's now reported a randomized Phase III trial of a PARP inhibitor olaparib compared to second AR targeted drugs, looking at both PFS and RPFS and overall survival in a CRPC population.

And the importance of that study is that not only did it show RPFS benefits, but also showed overall survival benefits as your colleague at Northwestern, Dr. Maha Hussain reported. And that is important. The other thing that's important about it is that the PROfound study that was done included patients with a pretty broad spectrum of mutations in the HRD pathway. And that's in contrast with rucaparib, which to date has only been approved for patients with BRCA1 and BRCA2 alterations in the post-chemotherapy setting. So they have a very sort of different, for now, spectrum of clinical utility. And we await further data with rucaparib in that pre-chemotherapy setting to mirror the effects of olaparib in the PROfound study.

However, for physicians treating a patient with a BRCA1 or BRCA2 alteration in CRPC, there are two choices, rucaparib or olaparib. For patients with the less common mutations, a RAD51B, ATM, a whole list of them, PALB2, et cetera, olaparib is really on label in those cases, as opposed to rucaparib. We will see as time goes on if these approvals expand, but it is an exciting time. The issue is of course with PARP inhibitors, we do see a pretty broad spectrum of responses. We do see some fairly profound responses and we're still kind of working out what is the mutational profile of the situation where we have a profound response to no response. And I think that was a little bit of a surprise that the response proportions to patients to PARP inhibitors, even when they have these important mutations, is really 50, 55, 45% range. So still a lot to learn about this class of drugs and still a lot to learn about this class of biomarker strategies in DNA repair alterations.

Alicia Morgans: I agree. And I think one of the things that was most interesting is that rucaparib was approved on the TRITON2 trials data, which is really a Phase II study. So more data to come in that, of course, but also in the TRITON3 study. And I know you're involved with some of this work. Can you enlighten us on what to look out for regarding that?

Charles Ryan: Well, I just want to touch on this point that you made, which I think is really exciting, which is that for the first time in prostate cancer we have a drug in CRPC that's approved, not on a randomized Phase III trial, but on a Phase II single arm study. And the reason for that is that they were able, the investigators in TRITON2, and yes I was one of them, but more importantly, the design of the study was to identify patients based on a biomarker, to identify a clinical benefit based on response of lesions with measurable disease. And that's a big deal. The question is whether or not we're going to have a lot of approvals now they've come down the pipeline that use this design or not, but really the key for why rucaparib was able to do it as a couple of things.

One is it's approved in other settings, in ovarian cancer for example. Two is it has a biomarker linked to response and I think that's the key. Therapies that we've been using for a long time, enzalutamide, abiraterone, we give them to everybody on the assumption that 70% are going to respond. We don't have a biomarker that selects for patients who will versus will not respond. So we'll have to see what happens with that idea, but it's kind of exciting that the FDA approved it on this basis.

Alicia Morgans: I completely agree. And I just think that there's going to be a lot more to come. Certainly, as we look forward to 2021 and beyond, we will hopefully have more information, as you mentioned, on those exploratory analyses that help us understand which of these DNA repair defect mutations or HR mutations are going to be the ones that really are drivers and those that we can target effectively with these approaches and which are really just going along for the ride. And before we move on, can you elaborate just a touch on TRITON3? What is that study design? What should we look for in that?

Charles Ryan: TRITON3 is for CRPC patients who have received either docetaxel or an AR inhibitor, but not both. And it's a randomized, two to one, rucaparib versus physician's choice of therapy. And it's enrolling patients with BRCA1 and BRCA2 mutations and approvals coming along. And I don't know when we'll have data on that, but it would be the next phase, if you will, for rucaparib potential approval in prostate cancer. And of course, there are other PARP inhibitors, right? Talazoparib and niraparib and a whole host of others that are making their way through the pipeline that we shouldn't ignore. So I think that we're going to get to a time when we have a choice of PARP inhibitors for clinicians treating prostate cancer.

Alicia Morgans: Absolutely TALAPRO, GALAHAD, and others are ongoing trials. And I think there's a lot to look forward to and a lot for us to offer to our patients as we're enrolling folks in clinical trials. So fantastic. Thank you for reviewing that. And as we think about that and we're looking forward, there were some other big pieces of data, actually three big pieces of data, that came out of some studies looking at patients with non-metastatic or M0 CRPC. The ARAMIS trial, the PROSPER trial, and the SPARTAN trial, all three of these reported overall survival data for patients who were treated with ongoing ADT plus either darolutamide, enzalutamide, or apalutamide versus ADT alone for that non-metastatic CRPC setting. What are your thoughts on this, and has this changed your practice?

Charles Ryan: Well, it certainly changed practice, and I have a lot of thoughts. I would say there are three points to make about the non-metastatic space. The least important point is the approval of the three new drugs. I mean, it's incredibly important that we have these three new drugs, but it also teaches us something about the disease. So while it is important that we demonstrated that we can delay metastasis by targeting AR targeted drugs, as these trials mature, it's becoming like, "Okay, not as much of a surprise, not a big surprise that would be the case." However, these drugs also improve survival, darolutamide, apalutamide, enzalutamide. And that's a big deal because it validates this idea of early versus deferred treatment. And I think that's incredibly important.

And so now when we are faced with a patient who's thinking, "I really feel fine. I don't have any symptoms of my disease. All I have is a climbing PSA, and I'm going to take a drug that may have side effects. Is it worth it doctor?" Right? And now we haven't answered that question that we can manage side effects. You and I are working on studies in that regard, but earlier therapy will not only prevent your bone scan from becoming positive, which is a big deal, it is likely to reduce your risk of death from prostate cancer, huge deal. The third part about the non-metastatic story is we will look back on this conversation in a few years, and we will say, "Boy, that was quaint when we thought it was non-metastatic disease," because we have so much imaging now that's coming along that's demonstrating that there's really very little such thing as non-metastatic disease. 

There's a really fascinating paper, it was actually published in 2019, but I think it kind of made an impression on me in 2020. And that was from Wolfgang Fendler and colleagues in Germany. And they took patients who were enrolled in the SPARTAN study, so by definition had non-metastatic CRPC, had a PSA doubling time of less than 10 months. They did PSMA-PETs on 200 of them. And 196 of them had disease on the PSMA-PET and a good proportion of them had disseminated multifocal disseminated disease on PSMA-PET. In fact, that's about half of the patients.

And so the reality is non-metastatic disease is really a situation of undetected metastatic disease. And we will look back when we get the new imaging that's rolling out, and that should bring up our next topic of conversation. The imaging will reveal that these patients do have metastatic disease, and the fact that we can identify it with PSMA-PET and other imaging modalities suggests that we might be able to integrate more focal therapies into that approach. And so there's a study underway called the PILLAR study, in which patients are actually getting stereotactic body radiotherapy to oligometastatic lesions detected by PSMA and treated with an AR targeted drug apalutamide. So it opens up a whole new series of potential studies that we can be doing and ways that we can seize on that idea of early treatment benefiting our patients greatly.

Alicia Morgans: Absolutely. I think just to emphasize the point that you made about this earlier intensification of therapy may provide benefits that we're really unable to make up for, no matter what we do in terms of subsequent therapies later on down the line. And I think it's also really important to just emphasize as you just did that these are clearly patients with very, very low volume metastatic disease. They're not non-metastatic. And if you talk to the folks who coined that term non-metastatic, they knew it at the time, they just didn't have a way to detect it and that was a phrase that was available to them. So agreed, there will be some changes that we'll need to make, I think, in our nomenclature over time. Yes?

Charles Ryan: But it's also a really important step in this discussion that the field has been having for decades, which is, should we defer treatment because treatment has a cost and it has side effects? And back in the 1990s, you would wait for a patient to get pain from his metastatic disease before you'd integrate therapy. And some people still were clinging to that idea in that, even when abiraterone and enzalutamide came out. There we demonstrated that you should treat patients before they get pain because you can delay the pain and things like that. Now we're saying you should treat patients with CRPC even before they get metastatic disease. So I think that it's really gratifying to see that. This is also coupled with developments in the treatment of castration sensitive disease, et cetera, and hopefully, we'll move into even earlier adjuvant, neoadjuvant phases of the disease. There are studies that are maturing and they are looking at those as well.

Alicia Morgans: Agree. And I do think one thing to look out for in 2021 and beyond, is going to be the combination from my perspective of these local therapies, SBRT, in most cases, I would think. Maybe some surgical approaches, to really trying to target the disease that we can see, but then also coupling, at least for a period of time I think, maybe with this intensified hormonal approach, because I am not ready to give up on that benefit that we see, that hormonal or that overall survival benefit with that intensified hormonal approach. But do find it so compelling that if we can eradicate any areas of disease that are visualizable, that we really might sway that survival curve and really change the trajectory of the disease. I think that is something that I look forward to seeing as time goes on. And to your point, too, were you going to say something else on that?

Charles Ryan: I look forward to seeing that data. I would say that I am a little skeptical that the oligometastatic radiation treatments are going to move the needle a lot. They may move it a little. I think that the PSMA PET data, circulating TTC data, and other data, suggest that really we need to think about this as a systemic condition, but I think I welcome the studies.

Alicia Morgans: Well, that's what I would say too, that really the systemic intensification we know improves survival, so I'm not really able to give up on that, and I want that benefit too and I am eager to see if SBRT or other approaches, in addition to that, may further bend that curve. But I guess neither of us knows, and we'll just have to see, but really to kind of continue along that vein, as you mentioned, imaging, particularly PSMA imaging, has been pretty hot in 2020 and really exciting in helping us in terms of identifying these areas of metastatic disease that we did not previously know about. What are your thoughts on those emerging imaging modalities and, of course, the approval, at least at UCSF and UCLA, of the Gallium PSMA?

Charles Ryan: Right, so it's a late-breaking event here, and I think it was November, December of 2020, that the FDA approved a Gallium-68 PSMA PET scans for patients with localized disease entirely or serologic relapse after local therapy. It is interesting that this was an approval that really only applied to two centers, but that's a great way to open the door I think. The Gallium-68 PSMA PET technology is something that is kind of slowly rolling out across the country and people are getting the ability to create the isotope and do the images. Should we see lutetium-based PSMA targeted therapies roll out in the coming year, that will be something that would be of interest to see more wide dissemination of the Gallium-68 PSMA PET. I predict that in the coming year or two, we will see most of our centers, academic centers, for sure, will have Gallium-68 PSMA PET, and that it will be a tool that we use to identify patients for potentially lutetium based PSMA therapy in the metastatic CRPC setting, which is entirely different from the current approval of the Gallium-68 PSMA PET, which is in localized and serological relapse.

Alicia Morgans: Yeah, I think it was interesting to me though, too, at least at those two sites where Gallium PSMA was approved, it's a pretty broad label. Anyone who's at risk of metastatic disease, I think is sort of how it was phrased.

Charles Ryan: Yeah, good point. Yeah.

Alicia Morgans: [inaudible] and biochemical recurrent, there's little room there in terms of using that technology. I thought that the PYL PSMA data that we saw this year, Michael Morris presented that, was also really compelling and was really interesting, and I believe that that is under review and hopefully may be` available for us at some point, as we look forward into 2021. That study that was presented, that CONDOR trial, was really in the biochemical recurrence setting, but was so nicely presented and so nicely done in terms of that positive, predictive value if we did have this positive PSMA imaging, these abnormalities showing up, that these were by that gold standard of truth, essentially, in most cases, truly representative of metastatic disease. And, of course, even, we're able to then change the clinicians' treatment plan for better, for worse. We don't know if that was a good thing or not, but at least they had more information and could make what they thought were better judgments. What were your thoughts on that study?

Charles Ryan: Right. Just for listeners, 18F-DCFPyL is a lysine urea-based small molecule, so it's still kind of a small molecule idea that targets PSMA and it carries F-18. There was a study called the CONDOR study that you mentioned that was presented at ASCO, which was for patients who had had local therapy in the form of radical prostatectomy or radiation, and had a rising PSA, and had negative or equivocal imaging for their setup. So it does demonstrate a fairly high degree of positivity with the DCFPyL and importantly, 64% of the patients in that study had a change in the intended management after undergoing the DCFPyL. What was also interesting is 79% of those were attributed to positive PYL scans, then 21% to negative PYL scans.

Some patients went on to receive salvage local therapy, some patients went on to get systemic therapy when they would have originally gotten salvage local therapy. This is what imaging should do for us, right? It should help us to spare the patient who is not going to benefit from radiation, the radiation. It should help us to spare the patient who doesn't quite need systemic therapy from getting systemic therapy. Kudos to Dr. Morris and the team there who designed a very smart study that really got right to the heart of not only what does this show us, but what does this force us to do, or what does this enable us to do, is I think the key way to think about it.

Alicia Morgans: Agreed. As we wrap up this portion of our where we are in 2020 and where are we going in 2021, let's just comment briefly on the lutetium trial, which of course is another PSMA targeted agent, but this time, not an imaging agent that lights up as we've heard some people describe, like a light bulb showing us where things are, but more like a bomb that obviously is there to really target and then destroy the prostate cancer cell. In the TheraP trial, we saw from the ANZUP group, these patients who had metastatic CRPC, who had already progressed on docetaxel chemotherapy and AR targeted therapies, were randomized to receive cabazitaxel or lutetium, and they had a PSA endpoint in this phase two trial that was also reported, I believe, at ASCO this year. What are your thoughts on that TheraP trial?

Charles Ryan: Yeah, so it suggests that lutetium may have a favorable role compared to chemotherapy. You pointed out the potential problem with that data, which is they used a PSMA targeted therapy, and looked at the PSA endpoint. So it's not exactly the hard data we want in terms of metastasis prevention or palliation or overall survival, but it certainly suggests and confirms our potential belief that PSMA targeting with lutetium may be an alternative to chemotherapy. In particular, what this holds out hope for, is for patients who are not candidates for chemotherapy, they may be able to receive this treatment. So a lot of work going on with lutetium, as we know, and I think that's one of the areas that we're going to look at in the coming year.

Alicia Morgans: Yeah. And just to recap too, I think that the adverse event profile really seemed to favor lutetium in this setting. Now, of course, we're pitting a chemotherapy against a PSMA targeted radiopharmaceutical, so not especially surprising, but important that it was measured and important that we can actually reflect on that as we're helping patients make choices, potentially depending on where this approach ultimately goes. The other piece that I want to emphasize that I think may be sort of a direction that we end up moving as we improve our imaging techniques over time in 2021 and beyond, is that to be selected for this trial patients actually had to have two PET imaging studies done. They had to have a PSMA PET that would, of course, light up when they had the PSMA binding in those cancer cells, but they also had to have an FDG PET study done.

It was really the combination of disease between the PSMA positive disease and the FDG positive disease that helped them select which patients were actually most likely to benefit from the treatment. Certainly, for patients who had predominantly FDG avid disease and very low PSMA expressing disease, this was not going to be a therapy that would be expected to be highly efficacious for them. So really, those patients who were enrolled were patients who had a high level of expression of PSMA, but a low level or at least a lower level of FDG avid disease, which I thought was really interesting, and hopefully will be something that we can continue to pursue in the future as we try to understand the heterogeneity of this disease and really target our treatments most appropriately.

Charles Ryan: That's a really important point. I think you've touched on the upcoming conversation we in the field will be having about tumor differentiation, right? This is something where the clinicians out treating patients don't think about this a lot, but in academic circles has been discussed more and more about well-differentiated tumors, making more PSMA perhaps. There's been a whole conversation, obviously about neuroendocrine prostate cancer, anaplastic prostate cancer, lineage plasticity has been studied and written about in the last few years, and this is the product of successful treatment with enzalutamide, abiraterone, et cetera. We are forcing the disease to take on a new space. I think that this FDG story and this PSMA story, where if you have FDG positivity and PSMA negativity, you have a different kind of prostate cancer, right? So I think we're just at the very beginning of thinking through that biological story, which will be a really exciting one to tell.

I think also it's exciting about the PET scans. Another conversation is the rollout feasibility, applicability in the community of all of this because what you're seeing here are some really impressive results from some very thoughtful investigators at a couple of very selected centers, and that's our job as researchers. But we also have to figure out how we're going to get that type of thinking out into the places where the patients are actually being treated, many of them.

Alicia Morgans: I 100% agree because effectiveness in a population in the real world is really that combination of efficacy and our ability to enact those protocols in our clinics with the patients that we see every day, and the difference between those can sometimes be pretty huge. It's going to be incumbent upon us to make sure that we do everything we can to make those therapies that we study in our trials as effective in real life as we possibly can, and hopefully, we'll be able to make that possible for our patients. So let's wrap this up and we'll talk more in the second segment.

Charles Ryan: Thank you. It's always a pleasure.

Alicia Morgans: Thank you.