Neeraj Agarwal: Hi, my name is Dr. Neeraj Agarwal. I'm a medical oncologist and a professor of medicine at the Huntsman Cancer Institute, University of Utah. I'm so honored to have two of our esteemed colleagues, Dr. Rana McKay, professor of medicine at the University of California San Diego, and Dr. Josh Lang, professor of medicine and a GU medical oncologist at the University of Wisconsin, Madison. Welcome.

Rana McKay: Thank you so much for having us.

Joshua Lang: Thank you.

Neeraj Agarwal: So it has been such a great 2025 United States Prostate Cancer Consensus Conference so far, and we have discussed so many topics on which there's no level one evidence. One of them, all of us encountered them in the clinic, is small cell prostate cancer or neuroendocrine prostate cancer. I often get... Not unusually I get call from my community colleague that I'm seeing a patient with small cell localized prostate cancer and no evidence of metastatic disease. What should I do? And frankly, I do not know. So I'll ask you for... Regarding how you practice, ask for your guidance on... For us, for all of us, how do you practice? So Rana, I'll start with you. So you have a relatively young man, localized prostate cancer, presenting with obstructive urinary symptoms. Biopsy shows small cell prostate cancer. What do you do next?

Rana McKay: Oh, thank you. I think we encounter this question a lot and there's really a lack of level one evidence of what to do and we are leaning into what is done in other diseases, in other contexts in lung cancer when the disease is localized. I think the first piece I would break down the management into what are the diagnostics that I need to confirm the diagnosis and make sure that what I'm dealing with is in fact pure small cell of the prostate or some other thing that's going on. So I think beyond the biopsy, it's making sure there's a second look. Is there any adenocarcinoma component? What's the patient's PSA? Doing appropriate staining, ensuring that the primary is in fact in the prostate, not anywhere else. So I think first it's the diagnostics and staging.

And generally my approach, and we're going to get into that, is to be fairly aggressive with these individuals. They can have very locally advanced disease, like you said, this gentleman presented with obstructive urinary symptoms. Where I like to integrate chemotherapy, I like to integrate local treatment, whether that be surgery or whether that be surgery followed by radiation or a pure radiation strategy, and a lot of the integration of surgery depends on the type of symptoms that the patient has, their age, and their fitness for surgery. But I generally, if somebody's obstructed, they're probably going to benefit from a surgical decompression, whether it's a TURP or other procedure to begin with. So that's my generalized approach, and I'm sure we're going to go deeper, but yeah.

Neeraj Agarwal: So before we go to the treatment, Josh, what do we do as far as staging is concerned? So Rana mentioned systemic staging. How often do you look for... Do a brain MRI, for example, in these patients? Is there a role for PET scans for these patients beyond CT and bone scans? So what is your practice?

Joshua Lang: So it's an excellent question and it is one of the greatest challenges for localized small cell prostate cancer because the vast majority of these patients will not secrete PSA. So they present with clinical symptoms in the absence of some other more standard screening approaches, which also means given the high proliferative rate as well as the high likelihood of this cancer to metastasize, that these patients, if they don't have overt radiographic metastases, they're still very likely to have subclinical metastases. So conventional imaging, CT scan, bone scan, all very appropriate. But this is really that clinical setting where you want to look, again, make sure that you're very confident before you recommend local therapy, but this is not a patient who has metastatic disease elsewhere, including the brain. So again, similar to how small cell cancers are managed in other diseases, we need to do the same thing for small cell prostate cancer. So it does include a brain MRI. And if there's a suspicion for other extraprostatic disease, an FDG PET scan is very reasonable to perform, because again, that first decision is absolutely critical for these men.

Neeraj Agarwal: Thank you. That was very comprehensive. So now moving to the treatment of these patients. If we have determined that patient has localized small cell carcinoma of the prostate, what is the next thing we should do from the treatment perspective?

Rana McKay: No, very good question. So if it is a pure small cell, there's no adenocarcinoma component, and the PSA is normal, I don't utilize ADT for these individuals. I don't think it has a role. I assess them for their eligibility for platinum, between cisplatin versus carboplatin, and I generally try to give them cisplatin etoposide up front. I think one of the biggest questions that tends to come up is how do you integrate the radiation and do you do a neoadjuvant strategy with EP, cisplatin etoposide, decompress them because usually they're presenting with some sort of obstruction and they're not going to be able to jump into radiation right away until they're decompressed.

And then once you've given them three to four cycles of EP, then integrating the radiation at that time point. And then another question comes up when you integrate the radiation is do you give them concurrent chemotherapy as a radiosensitizer? There's very limited data there. I think a lot of times we're extrapolating from the lung data on using concomitant platinum in that context. But I generally start with systemic treatment. If they have obstructive symptoms, they may require a simple prostatectomy or a TURP to kind of decompress.

Neeraj Agarwal: So systemic therapy starting with platinum etoposide, three to four cycles, followed by radiation therapy and then radiation sensitizing therapy?

Rana McKay: Potentially.

Neeraj Agarwal: Potentially, okay. And you said no ADT?

Rana McKay: No ADT.

Neeraj Agarwal: For these patients.

Rana McKay: Again, if they're obstructed to begin with, you have to deal with the obstruction, and the chemotherapy is not going to work right away to deal with the obstruction. So they very well may need, like I said, a TURP or a simple prostatectomy or something to have it so that they're not having to be with a foley the entire time that they're on their systemic treatment.

Neeraj Agarwal: That's great. We'll come to the follow-up of these patients, but before that, any role of prophylactic brain radiation?

Joshua Lang: It's an excellent question and I think in the setting of small cell lung cancer, there has been some benefits for prophylactic cranial irradiation. There's no data in small cell prostate cancer, and I think that's where we struggle to understand also the incidence of small cell prostate cancer that metastasizes to the brain. So there is obviously toxicities that come with PCI as well. So we really need to be cognizant of that. It's not something that I standardly use, though if there are patients that I think are very high risk or there's some other feature, it's certainly reasonable to consider. But again, we don't want to be delaying systemic therapy for these patients. And then if we follow that with treatment of the primary tumor, oftentimes these men will still progress outside of that. If they're not cured, they will progress. So we have to be monitoring these men very closely. And again, don't delay reinitiation of systemic therapy for PCI.

Neeraj Agarwal: Once we are done with the systemic therapy, how should we follow up these patients, doing what kind of scans?

Rana McKay: Very good question. I mean, these are the patients that I treat with serial imaging like we do for most solid tumors, where there isn't necessarily a blood-based biomarker that we're following. I get imaging on them at least every three months, the first year from completion of therapy, and then space out there afterwards because of... You're not going to use PSA as a biomarker, that's not really going to guide you, so I don't serially scan with FDG PET. But I will get an FDG PET if I see something that isn't conclusive that we need to further tease out on imaging.

Neeraj Agarwal: So continuous CT and bone scans, is that what you're suggesting?

Rana McKay: I think the bone scan is actually... Not to say a little bit questionable, the bone scan is something that we do in the context of adenocarcinoma because there's a propensity for-

Neeraj Agarwal: Osteoblastic.

Rana McKay: Prostatic, right, exactly. But that's not necessarily the case with pure small cell. So I don't necessarily think that these patients must undergo a bone scan concomitantly. That's not necessarily how we follow small cell lung cancer patients.

Neeraj Agarwal: So CT scan on the chest, abdomen, pelvis?

Rana McKay: Yeah.

Neeraj Agarwal: That's great. Let's see if the patient does not have small cell, pure small cell, but does have some adenocarcinoma component, anything changes for you, Josh?

Joshua Lang: That does change things a great deal. It's so vital that when we identify those evidence of neuroendocrine differentiation, which are often maybe smaller cells histologically, but we're often seeing expression of synaptophysin or chromogranin-A. But again, still PSA producing adenocarcinoma components. Molecular testing absolutely critical for these patients, and we still, again, should approach them as a very high risk disease, but one that still has a greater chance of curative intent therapy with local treatments, which that's where we think about combination hormonal therapies with radiation, whether that's along the STAMPEDE approach. But this is really where curative intent, I think we still have a greater chance than that pure small cell prostate cancer.

Neeraj Agarwal: So that adenocarcinoma component can shift the treatment more towards traditional prostate cancer treatment. And in that case, what is the role of platinum and etoposide therapy if they still have small cell component or neuroendocrine component?

Rana McKay: So I think if they're an admixed adenocarcinoma with neuroendocrine features, I am not necessarily using EP but rather using a taxane-based regimen with a platinum, whether that be cabazitaxel carboplatin or docetaxel carboplatin with ADT, and if they're high-risk localized, also adding abiraterone based off of the STAMPEDE data and giving them an extensive course of treatment. I think the question comes up around, again, how do you integrate the chemotherapy aspect in that context? In the localized setting, I'm generally integrating it post-completion of the radiation as opposed to giving it pre-radiation-

Neeraj Agarwal: For pure small cell.

Rana McKay: ... for a pure small cell, yeah.

Neeraj Agarwal: Very interesting. And last question, regarding neuroendocrine differentiation. It's highly uncommon to see neuroendocrine de-differentiation of adenocarcinoma in localized prostate cancer setting. Any changes? So I understand your point that we want to target both adenocarcinoma and the neuroendocrine type or small cell component, and that's why you want to use a taxane plus platinum rather than platinum plus etoposide. But what if it is neuroendocrine differentiation? Does it change anything for you, Josh?

Joshua Lang: It's a great point. I think one of the areas that I'm very cautious of, especially in the staging perspective, is the use of PSMA PET in patients who have neuroendocrine differentiation. Our chances of missing extra prostatic disease do increase in the setting of neuroendocrine differentiation if we're relying solely on PSMA PET. So we need to be very thoughtful from a diagnostic perspective. The molecular testing I think is very informative as well. And if this is something where there's acquired genomic alterations that may be different from the initial presentation, that's something else that can also very much influence what we would recommend for interventions. Coming back to that idea of do we now need to bring in that combination neoadjuvant therapy with chemotherapy-based regimens and then also how we integrate treatment of the primary tumor with radiation as well?

Neeraj Agarwal: Well, we just had a snapshot of treatment of small cell localized prostate cancer and also neuroendocrine type localized prostate cancer from the two well-known experts, international experts on this condition. So thank you very much for sharing your expertise and for enlightening us. Any last comments?

Rana McKay: I think that this is a disease that requires a multidisciplinary team to help treat. It's not in a silo of medical oncology or radiation oncology or urology, but it really requires multidisciplinary integrated care for these individuals and actually integration with pathology and radiology as well.

Neeraj Agarwal: Josh?

Joshua Lang: Well, thank you for the opportunity. This has been really exciting and to be here with my colleague Dr. McKay. I am excited about the opportunities as new therapies are being developed for small cell prostate cancer in later stages of disease, that we have opportunities now to move those earlier in treatment for these men with localized diseases as well. So there is great hope for the future.

Neeraj Agarwal: Thanks to both of you for sharing your expertise on how to manage small cell type and neuroendocrine type localized prostate cancer. Really appreciate your expertise.

Rana McKay: Thank you.

Joshua Lang: Thank you.