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PSMA-Targeted Radioligand Therapy for Metastatic Castration-Resistant Prostate Cancer

In this video, Drs. Celestia (Tia) Higano, Julie Graff, and Neal Shore discuss the role of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy in the treatment of metastatic castration-resistant prostate cancer. The patient is an 81-year-old man with 13-year history of prostate cancer who had received multiple prior lines of treatment for his metastatic disease, but no prior taxane. After his PSA rose again, he opted to travel abroad for lutetium (Lu-177) PSMA therapy, since he was not eligible for trials in the United States. The faculty discuss the VISION trial and the current and future role of PSMA-targeted radioligand therapy in prostate cancer.

Editor’s Note: This video was filmed prior to the FDA approval of Lu-177 PSMA radioligand therapy on March 23, 2022.


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Transcript

Disclaimer: This video transcript has not been proofread or edited and may contain errors.
Dr. Higano: Hi, welcome to The ASCO Post Roundtable Series on Updates in Prostate Cancer. My name is Tia Higano. I'm a medical oncologist and adjunct professor at the University of British Columbia. Joining me today are two of my favorite colleagues. Would you like to introduce yourselves? Dr. Graff: Sure. My name is Julie Graff. I'm an associate professor of medicine at Oregon Health and Science University. I'm a medical oncologist and also work at the VA Portland Healthcare System. Dr. Shore: Hi, Neal Shore. I'm a urologist. I'm with GenesisCare US as the CMO in urology and surgical oncology, and I'm the medical director of Carolina Urologic Research Center. Really great to be here with Tia and Julie for The ASCO Post Roundtable Series. Dr. Higano: Thanks. Our fourth case today will focus on the role of PSMA-targeted radioligand therapy in the treatment of metastatic castration resistant prostate cancer. We all know from our patients that this is a big topic, not just for us, but for them as well. This is an 81-year-old man with a long 13-year history of prostate cancer. He was originally diagnosed in 2008 and had a radical prostatectomy with T2aN0M0 disease, Gleason 4+4, and a PSA of 3.58. About four years after diagnosis, he was treated with SBRT to a lesion in his prostate bed that was seen with a C-11 choline PET, which is one of the only things we had at that time that was clinically available. In the following year, he started ADT with his choice of therapy, degarelix. Then after four years on ADT, he ultimately developed oligometastatic CRPC, so his PSA was rising and he had some new spots on bone scan. Now, he chose to be treated annually for three years in a row with SBRT to a few new oligometastatic lesions and stayed, of course, on his ADT, but after the last round of SBRT, he was advised to at least get some sip-T, which he did. But the following years, PSA was going up again and he chose to be treated with darolutamide, rather than more conventional enzalutamide or abiraterone, which were clinically indicated at that time. After a brief response, his PSA went up to 32.5 and he again decided that perhaps if he just switched from degarelix to relugolix this might result in a response. The reason he gave, which was actually true, was that after all these years of having degarelix injections, he had a rather leathery abdominal wall because he frequently had severe injection site reactions that led to some fibrosis there. He started relugolix and was certainly happy about that, but he wasn't eligible for any trials in the US, mainly because he had chosen not to have a taxane before. So he flew off to Vienna where he and many of my other patients have also been able to receive lutetium PSMA therapy. I just want to stop there in this case and ask if you have had similar kinds of patients who are, I would like to say, self-directing their therapy under your supervision? Dr. Shore: Yeah, it's interesting. He went with the darolutamide, which was not approved for mCRPC. It's a very good drug and I've been privileged to be part of the trial and the ARAMIS trial for nmCRPC and then the recent ARASENS trial. We're doing a whole bunch of other trials. I can understand maybe he was impressed with the data on the lack of cognitive effects because of the lack of blood-brain barrier, drug-drug interactions, but still nonetheless, it doesn't have in its label right now mCRPC, so he had to pay presumably out of pocket and then going and flying over to Europe to get the lutetium PSMA because it's not approved in the US currently. I don't think any of these things that he did was not without reason. In fact, seems pretty reasonable. But for me personally, where I am in the Southeastern part of the United States, I don't really have a lot of patients who can have that financial wherewithal to do this. We did participate in the VISION trial. I'm super excited about the pending, hopeful, the any day now approval by FDA based upon the wonderful work of the VISION trial, as was presented by Oliver Sartor last year at ASCO with a simultaneous New England publication. I think we're all, in the US, anxiously awaiting. So many of our colleagues in Germany and Australia and a few other parts of the world have had great experiences with PSMA RLT therapy. I think it's a really, really important therapeutic class that hopefully will become global in its accessibility. Luckily for this particular patient, he actually did quite well. He had his three infusions, and a follow-up PSMA PET in this country showed that all of the lesions were responding. By four months after starting his Lutetium PSMA, PSA had fallen to 3.37, and I suspect it's going to continue to fall for a while longer. Now, Neal, you were mentioning you were involved in the VISION trial. Maybe you could give us a sense for who you think is going to be eligible for treatment, which I assume will be based on eligibility for the VISION trial. Dr. Shore: Yeah. If you looked at the inclusion exclusion criteria, the patients were pretty beat up and they had high tumor burdens, a lot of previous therapeutic treatments. They had to have had at least a taxane as well as at least one novel hormonal agent. Many of them had had at least two taxanes and had had more than one novel hormonal agent. They were high tumor burdens and a lot of prior therapies. Now I don't know what the label will read. If it'll follow that strictly mCRPC with an absolute insistence on prior taxane as well as an NHA, maybe it'll be insistence upon an NHA and if not prior taxane, maybe now taxane ineligible. Hard to really know until we see the actual label. The good news is there are several trials going on right now in North America looking at pre-chemotherapy mCRPC for PSMA RLT therapies. There are even some PSMA RLT therapy -- radioligand therapy -- and even mCSPC in the metastatic population. As Julie said, we have five distinct mechanism of action therapeutics, and the PSMA conjugates with our radiation ligand therapy, it will be the sixth. To your point, Tia, this is a huge advance in the arc of our career. I think this is incredibly exciting, this whole world of theragnostics. Dr. Higano: Right. As you said, there's many trials actually that are ongoing now with lutetium PSMA and other radioligands that I think will really expand the eligibility for treatment with this particular drug. I think the VISION trial is just the very beginning, is my guess. It's kind of interesting because I think this is the one place where the US has been far behind many other countries in looking at this treatment modality. I've had other patients go to Australia, to Germany, other places, so I think we had better of hurry up and catch up. Some clinical takeaways. One of the things is, like our first case, we talked about where there was a patient who really was in control of his destiny, I guess, so you could say, and so it's patients who advocate for specific types of therapy that may not be standard of care, it can be for pretty challenging, but my own philosophy has always been, look, if I refuse, unless I think this is dangerous for them, at least I feel like they're under the care of a competent medical oncologist who understands the disease. I don't want them to go off to somewhere else, so I try to give them the benefit of the doubt. I'll be there when something happens. We said Lutetium PSMA is likely to be FDA approved any day now and that new combinations with Lutetium PSMA will likely come to fruition in the next few years. Then there are other radioligands, as Neal alluded to. Actinium, which is an alpha emitting agent instead of lutetium, which is a beta emitting agent, these trials are all in progress and may actually be important for those who fail prior lutetium PSMA therapy. We don't know yet, but there's a lot of interesting things going on in this realm. Other key takeaway, either of you? Dr. Shore: This notion around a patient directing his or her therapy, I get that. Some of these folks, particularly this patient and his family may not have the time to wait for the trials to come out. This is a bad disease for some patients. We all know. We've all seen this and sometimes you've got to take the bull by the horns, as they say. We see this in malignancies, we see this in infectious diseases. Gosh, look at the challenges that the poor patients with HIV/AIDS had to go through for years where they were difficult getting access to studies. Now that's the same thing. I've actually become a lot more compassionate and understanding. But to your point, Tia, that we have to protect our patients from bad information and pseudo trials and pseudo recommendations. That is the challenge. Simultaneously, we have all these advances thanks to the great work that's done by so many of our colleagues all over the world. This has become quite complicated. It's not your grandfather's advanced prostate cancer anymore. This is complicated stuff. I remember, I had the pleasure sitting next to Johann de Bono, and Johann turned to me and goes, "Man, this is really getting complicated." When he says it's getting complicated, I'm like, "Yeah, it really is!" My point is we have to really, really empower the multidisciplinary team: the uro-oncologist, the medical oncologist, the radiation oncologist, the pathologists, the nuc-med radiologist, the primary care physician, physical social therapy, we have to really -- cardio-oncology, neuro-oncology. Because we have so many things, we have to really do our best and it's not easy, because we only all have so much time in the day and there are challenges logistically to do this, but that's the only way patients are going to get access to care and get the best care. Dr. Higano: Good points, Neal. Thank you. Julie, do you have any parting words? Dr. Graff: Briefly, I agree with Neal. I think multidisciplinary approaches are so important. I would say the guy directing his own therapy, what I worry about is them having three different medical oncologists and us being expected to keep up with the other two or something, but I like to be a partner to my patients and not shame them for trying something different. Dr. Higano: Right. Now, when there's numerous ones involved, I usually say they should probably pick one. Dr. Graff: Good. Dr. Higano: Okay. This brings us to the end of this case. Thank you both very much for your comments. Please see the other segments for further discussion about the latest data in prostate cancer or visit ascopost.com.
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