Exploring the New Landscape of mCRPC: PARP Inhibitors, PSMA Radioligand Therapy, and More - Alicia Morgans
November 22, 2022
Neal D. Shore, MD, FACS is the Medical Director for the Carolina Urologic Research Center. He practices with Atlantic Urology Clinics in Myrtle Beach, South Carolina
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
Neal Shore: Hi everybody. Neal Shore, the Chief Medical Officer at GenesisCare and a real passionate researcher in GU oncology. I'm so happy today to be interviewing Alicia Morgans, who's done so much in GU oncology. Alicia's at the Dana-Farber and she's directing so many trials and also particularly, an expert on survivorship and the work that she does amongst many things. Alicia, you just recently chaired a really great program at EAU on mCRPC. And I think you touched on many really hot topics and despite COVID, you've been pioneering so many amazing things, especially with your educational expertise, PARP inhibitors, PSMA radioligand therapy, the new landscape of things that are coming out. And can you tell us how that went, how was your EAU experience in this session, which I'm sure many people thought was fantastic?
Alicia Morgans: Well, thank you so much, Neal. I was just so honored to be there, co-chairing with Professor Laura-Maria Krabbe, and getting back to seeing colleagues around the globe. And in this setting, of course, we were in Amsterdam and just very happy to be there. And it was not necessarily as crowded as I have seen prior EAUs, but it was a hearty crowd and one that was really excited to be there and to learn collectively. In this particular session, we talked about so many aspects of metastatic castration-resistant prostate cancer, and there were multiple presentations that went through the standard approaches to treatment. And there was a really nice presentation by Professor Noel Clarke, who went through biomarkers that we might consider as we're recognizing responses to treatment or thinking about prognostic markers that might help us decide whether to choose this treatment or that. Of course, everything's still exploratory at this point, but very thought-provoking.
And then I spoke about some of the more recent trials that have been completed. Some of them presented as recently as GU ASCO, 2022 and ASCO 2022 to just update the crowd on those. I think to get started and just dig into some of that, I think obviously we've had PARP inhibitors available to us, olaparib and rucaparib, and there has been use really dependent at this point in time, on biomarker testing in terms of germline and somatic identification of HRR mutations that can be targeted by these medications. But the really exciting updates that we heard at ASCO GU included the use of these agents, olaparib and actually niraparib, in combination with abiraterone in the first line metastatic CRPC setting. And this was in the PROpel trial. This was with olaparib with abiraterone and the MAGNITUDE trial, which included patients treated with niraparib and abiraterone.
I think really exciting data to suggest that the combination of the PARP inhibitor plus abiraterone in both of these studies suggested that there was a longer radiographic progression-free survival with that combination, versus abiraterone alone in that first line metastatic CRPC setting. So really exciting, thought-provoking and makes us wonder whether there's a synergy or whether we might really attain that kind of progression-free survival advantage if we would sequence them. And that's still unclear. But one thing that I raised and pointed out to everyone was that, in the PROpel trial, we actually saw that the prolongation of radiographic progression-free survival seemed to extend to an all-comerspopulation that included patients who did not have HRR mutations. Now, of course, there are questions about how we apply this and whether we maybe shouldn't do genetic testing, germline or somatic at all anymore.
And I would say, certainly, it's too early to make definitive recommendations about the biomarker-negative population in everybody. But perhaps this is something that we might apply in those younger patients, hardy patients who, especially patients who have these HRR mutations, to think about these combinations and try to see whether we can do better for them. But I think there's a lot to dig into here, and genetic testing, germline and somatic is still recommended in the guidelines and is still standard of care and absolutely something that informs family members, as well as helps us predict how strong and robust that response to the combinations and single-agent PARP inhibitors are going to be. So we did focus a lot on that.
Neal Shore: Yeah, that's a great summary and I love the way you ended it by saying, look, it's still important to test, but isn't it interesting that now, one plus one could give us even better results if we combine, especially in the biomarker negative population. Clearly as you point out, PROpel met its primary endpoint and was highly statistically significant rPFS benefit, eight months more than just receiving monotherapy abiraterone with prednisone in that first line mCRPC space. So the survival data is still pending for its maturity. I think we're going to see some more further biomarkers analyses and some potentially additional OS information at ESMO, but the way you summarize that was really perfect. Alicia, what about, it's so exciting, so we're making advances in understanding the importance of doing testing. You clearly are saying testing is still important. We may be able to help patients who we can't get testing in, or where the testing is negative, by combining drugs of different novel mechanisms of action. But talking about other mechanisms of action, what about this other really burgeoning area of PSMA radioligand therapy?
Alicia Morgans: So agreed, this is so exciting. And I think as long as we can get our logistics in line and make sure that our SRPs are up and ready to accommodate rolling out things like Lutetium PSMA 617, it is here, certainly, it's been approved and it is something that we are excited to use with our patients. I did in this session, mention that the TheraP data was described at ASCO 2022. And in this trial, patients with mCRPC had received prior treatment with docetaxel chemotherapy, they had mCRPC, many of them had also been exposed to an AR targeted agent, a large majority of them had. And they were randomized to treatment with cabazitaxel or Lutetium PSMA 617. What we saw at ASCO 2022, is that there was no difference in overall survival in this phase two trial. Of course not designed with overall survival as a primary endpoint, but an important endpoint nonetheless.
So what we discussed in this session was, how that affects our thought process. I think the way that I think about it is that, these two agents cabazitaxel and Lutetium PSMA 617 are options for treatment of metastatic CRPC. There will be barriers in terms of patient selection, perhaps in identifying patients who may or may not be eligible for treatment with Lutetium. And so, for all patients who are not eligible and for some patients who want cabazitaxel first, perhaps, or who need to because of logistical reasons, cabazitaxel is still a great option and Lutetium PSMA 617 is a highly active treatment option as well. So it's nice to know that we have both of these, that's new data from ASCO.
And the other thing that I think is exciting is that, there is some data that suggests that SUV mean, which is sort of the average SUV of all of the voxels in the patient, not a standardly reported metric, but something that might be reportable in the future as technology evolves. This might help us identify patients who might have the most robust response to Lutetium SUV mean over 10, seemed to suggest the highest rate of response.
And this was something that was again, discussed at ASCO, both from the VISION trial and recapped from the TheraP trial as well. So really interesting. And as we have access to this, I think in our centers, small and large, I think this is going to be very much an integral part of our treatment algorithm for mCRPC.
Neal Shore: Yeah, I really like the way you analyze that, because you're bringing in the real-world conundrums that we have. Do you have access to the drug? Who's going to give the drug both for cabazitaxel and for Lutetium 617. But what's really great is that we have treatment options. And when I listen to you and the work that I've been fortunate enough to do with you and other colleagues, it's about really bringing in the multidisciplinary team, urologists and medical oncologists, but now nuclear medicine radiologists and radiation oncologists, in addition to the broader teams. So it's great for our patients with advanced disease, but we're not stopping there. You also, in your symposium and your presentation, you talked about all the other exciting things that are happening. There are a lot of other targets. Can you comment on those and what you're excited about?
Alicia Morgans: Sure. Well, I'll just briefly say that there are multiple other Theranostics coming down the pipeline. Many of these are targeting PSMA, but some of them are not, and these are different radioactive ligands that are attached here. Some of them are using different approaches to PSMA targeting. Some of them are antibodies, some of them are small molecules. And so, we've got a lot coming down the pipe in terms of radiopharmaceuticals. I would also say that, things like AR degraders are still being developed and we saw some exciting data that some of these may target patients who have specific mutations in the androgen receptor that may be resistant to many other treatment approaches, but may be sensitive to some of these AR degrader approaches. And it may be a tolerable option for them in terms of therapy, ultimately. And of course, our cellular-based therapies, whether they are PSMA targeted bites or whether they are PSCA targeted cellular therapies, are really exciting.
And there's a whole panoply of these really coming down. And I'm excited to see how we as clinicians, are able to modulate the disease-directed effects of these therapies while still trying of course, to keep some of our more vulnerable and frail patients safe during treatment. And so, we have a lot of work to do a lot of collaboration with our other colleagues in urologic oncology, as well as perhaps our bone marrow transplant and liquid oncology collaborators, to ensure that we do this, both in an effective and safe way.
Neal Shore: Yeah. Again, really well said. I think that all strategies to decrease resistance to the accepted, approved therapies, thinking about combinations, giving them in a way that is tolerated, maintains quality of life, patient reported outcome measures, which you've been really championing, it's really great work. So thank you so much for sharing your outstanding presentation that you performed at EAU and look forward to our ongoing work in 2022.
Alicia Morgans: Well, thank you so much for the opportunity, Dr Shore.