Emerging Radiopharmaceuticals and PARP Inhibitors in Prostate Cancer Treatment

In the sixth and final segment of our prostate cancer roundtable, Dr. Appleman leads a panel discussion with Drs. Mehta, Kelly, Chablani, and Wong on radiopharmaceuticals, including radionucleotide therapy, and the effect it has on patients. The discussion covers the future of radiopharmaceuticals, from T cell engagers to bite therapy to CAR-T, as well as how physicians can increase practical knowledge of predictive biomarkers for patients. Lastly, the roundtable concludes with an exploration of PARP inhibitors.

Watch this roundtable from the beginning: The Role of PSMA PET in Advanced Prostate Cancer Treatment Decisions

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Dr. Wong:
Now what if you had a patient who was on ADT plus enzalutamide for hormone-sensitive disease and their PSA is just creeping up, like they’re progressing, but not really quickly? Could you use this trial to convince yourself to just continue enzalutamide and add radium? It would be a kind of rare situation, but I’m just trying to think of how you could apply this data right now to our current patient population.

Dr. Appleman:
That’s a great point. I actually think there are a lot of those patients who’ve been on the combination, their PSA starts to go up and there’s not really radiographic progression for a while or it’s pretty minimal. You really don’t feel like it justifies switching to, let’s say, docetaxel. And I like that idea of thinking of it in those patients.

Dr. Mehta:
While you are on, Dr. Appelman, if you see next three or five years, what are the other radiopharmaceuticals you think will change our management? I hear, so now we have radium-223, we have Pluvicto, we have alpha emitters, we have a trial for that. So I think it’ll be very interesting and good options to have. But challenging for us as a clinician to make how to sequence the right strategy. How are you using some of the data and sequencing for the patient?

Dr. Appleman:
I feel like we’re still learning. And a couple cautionary thoughts is I think there’s only so much radionuclide therapy a person’s bone marrow can tolerate. And a lot of that depends on the volume of disease. And where I’ve really gotten into trouble is people who have near a super scan where I treat with one of the radioisotopes, the people who had real super scans as were excluded from some of the trials and the higher burden of disease people can really take a marrow hit.

The other organ that we’re abusing in some of these patients is the kidneys. And I’ve had patients who have gotten various, often investigational nucleotides like you mentioned, who are on dialysis now, and one of them had a micro angiopathic process in his kidneys.

So, that’s something that I know our nephrologists are partnering with us to try to study. And I think as we use the radionucleotides more, most of them are cleared renally. And I think the kidneys can only take 200 centigrade or they’re very sensitive to radiation. That’s something we’re going to have to watch and again, collaborate with our nephrologists.

Dr. Chablani:
Yeah, in the future is ripe with T-cell engagers and bite therapies.

Dr. Appleman:
Maybe CAR-T.

Dr. Chablani:
Maybe CAR-T. So I think it’s, yeah, radiopharmaceuticals and then this whole field of bites that are going to potentially expand survival for patients in the metastatic cancer-resistant setting even more.

Dr. Appleman:
And I hope that we can get smarter about predictive biomarkers for these patients, even docetaxel versus… we need better biomarkers for a lot of these agents, for radium, for lutetium, for… I guess we have PSMA for lutetium, but for docetaxel, for platinum, we need better biomarkers.

Dr. Mehta:
Yeah, I think as we eluded the topic of biomarkers, of HRD mutations and using the combination of PARP with the ARSI, but as we all know, the side effects of PARP inhibitors is also is the cytopenias. And so how you utilize that. So are you using in your patients when they have HRD mutation, are you using a PARP plus AR combo in a castrate-resistant setting or are you sequencing?

Dr. Appleman:
Great question. I think one caveat is that just as with radium, now that most patients are on it, ARSI in the hormone-sensitive setting, that we’re not treating them with… the most solid data are at the start of adding therapy for patients who are refractory just to a GnRH analog using the combination. But I think that the data presented at ASCO by Maha Hussein showed it was-

Dr. Chablani:
There was synergy.

Dr. Appleman:
Strong synergy for the combination. And I think if someone’s on an ARSI in the hormone-sensitive setting and they progress and you’re going to start a PARP, I think with those studies come out toxicity-wise, there’s not a big downside to keeping that ARSI or switching to another one, there’s not a big downside to keeping it on board or adding another one, I think.

Dr. Chablani:
Yeah, so that phase 2 trial that Dr. Hussain presented, it was like a small study, 20 patients in each arm. They got either abi/pred plus olaparib versus olaparib alone versus abiraterone alone. And then on progression, the patients… and everyone had to have, I think, BRCA 1, 2 or ATM mutation and hormone-refractory, like metastatic hormone-refractory settings.

So the patients that got the sequence, so they were allowed to cross over. So if they got abiraterone alone and they were allowed to go to olaparib on progression, or if they got olaparib alone, they were allowed to go to abiraterone on progression. And the radiographic progression-free survival, the primary endpoint of the study was twice as long, I think 30 versus 17 months or something, twice as long in the patients who got the upfront combo versus the sequencing approach.

So that’s kind of the only study that it’s a small study like 20 patients in each arm. But that’s an important study that tells us there’s some sort of synergy. So I think it’s very reasonable if a patient is metastatic castrate-resistant, has already been on abi/pred or enzalutamide, and then you find that they have a BRCA 1 BRCA 2 mutation, and they’ve had response to add the olaparib on and exploit that synergy that might be going on between hormonal therapy and PARP inhibition. And I myself have done that for a couple of patients.

There’s also the talazoparib plus enzalutamide combination as well. But yeah, PARP inhibitors have side effects. So at the end of the day, we also have to consider the patient and whether if they’re 90 years old, do we want to be putting them on talazoparib plus enzalutamide or yeah, just PARP alone. Obviously, talazoparib is not approved as monotherapy, but yeah.