Evolving Treatment Landscape of Nonmetastatic Castration-Resistant Prostate Cancer

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Comprehensive insight to key treatment modalities for patients with nonmetastatic castration-resistant prostate cancer and how to select amongst them.

Transcript:

Rana McKay, MD:Maybe that’s a great segue to nmCRPC [nonmetastatic castration-resistant prostate cancer]. What are your thoughts about this state? What’s happening to the state in the current era with advanced imaging, PSMA PET [prostate-specific membrane antigen positron emission tomography]? What do we think of the state now? Scott, with all your work in PSMA PET imaging, radioligand therapy, and so forth?

Scott Tagawa, MD, MS, FACP:Well, what I know is that patients that have nonmetastatic by, I don’t want to call conventional imaging, not including PSMA PET, because I think that is conventional, but we’ll call it modern imaging with the PSMA PET. Nothing has really changed in these patients who might have been on just LHRH [luteinizing hormone-releasing hormone] and have a rapidly rising PSA [prostate-specific antigen], and nothing on CT and bone scan. Whether or not I can see it on the PET, they should benefit from the addition of an AR [androgen receptor] signal inhibitor for 3 studies. It’s not just met [metastasis]-free survival advantage. It’s an overall survival advantage without a detriment in quality of life. That’s a nice trifecta to have there. Whether I happen to see 1 or 10 lesions on a PSMA PET, I think they should still benefit. I think all these drugs, regardless of the label, I think they also work in metastatic CRPC. I think that if we’re doing something different than giving them, I’m trying to think of the order of APA [apalutamide; Erleada] and DARO [darolutamide; Nubeqa] in terms of approval. If we’re doing something different than that we have to keep in mind, well, we’re deviating from level 1 evidence. Now we see a positive PSMA PET scan and we see 1 lesion. We all want to go after that. There might be individual reasons for worrying about systemic therapy toxicity or if it looks like slower doubling time. We’re more confident that it’s not all disease, but the biggest bulk of disease and [we] can delay something like that. That makes rational sense. Again, if I’m doing it, I’m telling myself and the patient this is a little bit off book.

Rana McKay, MD: Now we chatted about the 3 drugs that are approved in the nmCRPC setting. The 3 ARSIs [androgen receptor signal inhibitors]. What are the differences between these drives? How do you all select between 1 of them? We chatted a little bit about this for metastatic hormone-sensitive disease with APA [apalutamide; Erleada] and ENZA [enzalutamide; Xtandi] [and] here you’ve got 3 to pick from. Are they more similar than they are dissimilar? What do you think about these agents?

Arash Rezazadeh Kalebasty, MD:Go ahead.

Sumit K. Subudhi, MD, PhD:I tell my patients it’s like opening a medicine cabinet when you have a headache, and you have ibuprofen, Motrin, and Advil. But the truth is that they do have different side effect profiles. Based on the patient’s comorbidities, and also drug-drug interactions with their home medications, I will choose different ones. For the most part right now, from my experience, as well as the data … has shown that darolutamide appears to have the least toxicities.

Rana McKay, MD:I know that retrospective data from the DEAR study [NCT05362149] was presented by looking at the 3 agents looking at toxicity profiles. I think that pans out in clinical practice too. There are less drug-drug interactions. Barring fatigue, there seem to be fewer cognitive issues with darolutamide. Obviously, it’s a very personalized decision, the choice of around anyone given agent in that context. We’ve talked about what’s standard of care in this context with regards to the ARSIs. We’ve talked a little bit about the role of SBRT [stereotactic body radiation therapy], which seems to be an emerging modality that we don’t really have level 1 prospective evidence about how that may impact outcomes. Any other novel therapy strategies that are being tested? Scott, I know you were investigating the role of radioligand therapy in this context.

Scott Tagawa, MD, MS, FACP:We did a study in the older era, before we had any data, really. Actually, we had negative trials in that era with zoledronic acid and other drugs. We now know that we can squirt in something with something that lights up, and they’re positive. These are not micro-metastatic disease, they’re macro-mestatic on PET. If we can take something that lights up, what if we can take radiation there? We did a trial that we termed salvage radioimmunotherapy. Instead of just radiation to the prostate or pelvis, take radiation everywhere else. Studies funded by the PCF [Prostate Cancer Foundation] and the DOD [Department of Defense], it used an old-fashioned version of second mind hormone therapy with ketoconazole as the backbone. Everyone got the antibody, which has a little bit of efficacy of its own, and then randomized them to mostly an imaging agent as the control but does have some … emission, which is a very potent, very short range emitter versus the beta emitter that most people are familiar with now, which is lutetium 177, with the primary end point of 18 months met-free survival, and it met that end point in essentially this randomized proof of concept study. In the current era, because the systemic therapy with the ARSIs works so well, I think it would take a big study to show that, but I think there might be some opportunities with maybe some de-escalation studies. There might be other ways to go about it than just prolonging met-free survival by another year, which is great, but that’s a big study. I think it works. But I’m not sure where we’re going with that. Let’s say, sorry I keep talking but I’m extrapolating something that I just thought of. So the mCRPC, because they have a positive PSMA PET and we have approval for some of these agents in the pre-chemotherapy mCRPC setting, is that now on-label? I don’t know. But I can see people maybe starting to use that, but we don’t really have any great data in terms of efficacy. And we certainly don’t have a lot of long-term data in terms of toxicity. And these patients will live longer than the patients that have bigger volume disease.

Sumit K. Subudhi, MD, PhD:You’re right. There’s not a lot of data to help guide us on what the next steps should be. Sometimes I take this opportunity to add sipuleucel-T [Provenge] to the patient’s regimen because it has a narrow FDA indication. Asymptomatic, minimally symptomatic. Now that we’re using some of our best drugs upfront, the metastatic CRPC landscape has changed. So when they come off of those drugs, they may become symptomatic and you can no longer get sipuleucel-T, or they may have new liver mets or some visceral mets that preclude you from getting it. Sometimes I take that opportunity to sneak it in.

Rana McKay, MD:What are other people’s strategies around sipuleucel-T? I think the utilization across the board has been quite low—around 10%. I really view it in a setting where you don’t want to do anything to begin with, whether they’re having slow PSA progression or you just want to buy time that maybe that’s where you can sneak it in. And if you get a benefit you do. You never end up knowing whether it actually worked for any patient that you give it to.

Scott Tagawa, MD, MS, FACP:Because they’re alive.

Rana McKay, MD:You just give them their 3 doses and go.

Arash Rezazadeh Kalebasty, MD:Scott, I had a question for you since you mentioned that. It seems like you have to have enough volume or enough mass for PSMA lutetium to work. It’s really micro-metastatic is not going to work. Do I understand it right?

Scott Tagawa, MD, MS, FACP:Yeah, I think well, this is based on theory, so 2 issues. One is the targeting agents. A small molecule like PSMA-617 or PSMA I&T binds PSMA, is internalized, and then spits back out in a macro-metastatic lesion. Well, there’s a neighboring piece of a positive cell that just takes it up. If it’s micro-metastatic, it just washes away. That’s one part of it. You can use an antibody and that stays internalized. The other is not just lutetium, but a beta emitter, so relatively weak and with a path length that is too long for just a couple of cells at least in the hypothesis. I call PSMA-positive PET disease macro-metastatic, but rising PSA-negative PSMA PET does not mean there’s no cancer out there. It just means the volume is too low or gives me a negative disease. But in this setting, it’s usually the volume is too low. I think it’s a hypothesis that an antibody approach and/or with an alpha might work there. But yeah, I think the volume is too low to be optimal for a small molecule with lutetium.

Rana McKay, MD:That’s wonderful. That’s great. I know the field is evolving. We’re meshing mCRPC with CRPC. I feel like the state’s going to end up going away completely.

Transcript edited for clarity.

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