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Elena Castro: Hello, welcome to a new episode of Interdisciplinary Management for patients with prostate cancer. What is the newest state of the art in prostate cancer in 2024? My name is Elena Castro. I'm a medical oncologist at Hospital Universitario 12 de Octubre in Madrid, Spain. And today we will discuss a case on high-risk localized prostate cancer with Dr. Tian Zhang from UT Southwestern Medical Center in Dallas, Texas.

Tian Zhang: Wonderful. Thank you so much for having me, Elena, and the UroToday Group. I'm happy to talk through a case with you all about high-risk localized prostate cancer. So we'll talk through a case study and then talk about the current data that we have.

So this is a case that many of us are faced with in the clinic, a 72-year-old man who presents with urinary frequency and urgency, nocturia, with a PSA of 18 that has risen from 10 from six months prior. On transrectal ultrasound-guided biopsy, he had Gleason 9 adenocarcinoma, grade group 5, in 6 out of 12 cores. An initial CT abdomen and pelvis and bone scan were normal. It did not show metastatic disease. But on PSMA PET, there is a left external iliac lymph node that you see on the screen here.

So we take a quick look at the definition of high-risk localized prostate cancer, and we are always often faced with this case in the clinic where PSAs are potentially over 20, Gleason score 8 to 10, grade group 5, and T3 disease, so any cancer that has extended outside the capsule. But the newest challenge I think in managing these high-risk localized diseases is also thinking about patients with PSMA PET activity. So we've heard our Australian colleagues say that this is a more accurate representation of cancer that has spread, and indeed it is. We can see highly sensitive disease that's picked up on PSMA PET.

But this I think depends a bit on conventional scan correlates and thinking about whether or not we would've picked up metastatic disease on our routine CT and bone scans as well. So here you're seeing representative slices of pelvic lymph nodes, mediastinal lymph nodes that are not meeting size criteria, and also a T12 vertebral lesion that's quite avid.

So I think our Australian colleagues, Dr. Michael Hoffman and his group at Melbourne, have really done a nice job of thinking through PSMA PET versus conventional imaging. The ProPSMA study looked at about 150 patients in each cohort, to look at positive versus negative, in terms of both conventional scans as well as PSMA PET. And what they showed nicely I think, in this figure, is that for PSMA PET images and those in red versus conventional scans in blue, you see a bit higher sensitivity in picking up metastatic disease, both pelvic nodal disease as well as distant metastasis, as well as increases in AUC.

The specificity is less so on the primary analysis, but then on their secondary analysis and their sensitivity analysis, it does show a little bit more benefit from PSMA PETs. And so with that and multiple other studies that we're not covering today, the guidelines for thinking about scans for our localized disease for prostate cancer importantly updated to reflect the incorporation of PSMA PET scans. And so the NCCN, last updated in January of 2023, recommended PSMA PET scans for unfavorable intermediate-risk prostate cancer for high risk with Gleason 9 to 10 or PSA over 20, as well as for biochemical relapse and progression. And then you'll see all these PSMA PET scans also incorporated into the ESMO guidelines as well. And then finally, for the EUA, the PSMA PETs have been incorporated also for high-risk localized disease as well as for biochemical relapse.

So, taking another look at treatment for our high-risk localized prostate cancer now that we have identified metastatic spread to lymph nodes or to bone, the standard of care continues to be hormone suppression for 18 to 36 months, depending on where we practice, as well as definitive radiation therapy to the prostate. The question arises on whether or not to add an intensified treatment for AR-targeted therapy. And here, I think the STAMPEDE data has the best data showing the benefit of adding further AR-targeted therapies with abiraterone, with or without enzalutamide.

So, here we're showing you the data that was published about a year ago with the STAMPEDE cohorts, patients treated with abiraterone with or without the addition of enzalutamide versus control ADT alone for high-risk localized disease. And you see, based on both metastasis-free survival and overall survival, there was a benefit in intensifying therapy for these patients.

Elena, I think there's a question in the field, though, about whether or not we can hold treatment during these intensified treatment courses and what to hold. Should we at some point in the course think about holding androgen deprivation, or should we hold the AR-targeted therapy? Many of these trials were written without a stop date, and therefore it's hard in our clinics to interpret who we should be selecting and when we should be holding treatment.

All right, one more piece of data before we tackle our discussion. The LuTectomy Trial was an investigator-led trial from Dr. Eapen and her colleagues out at Peter Mac in Melbourne. These are 20 patients essentially who were treated with PSMA-targeted lutetium before surgery. The first cohort received only one cycle of PSMA lutetium, and then the second cohort, they added 10 more patients who received two cycles of PSMA lutetium prior to surgery.

You see their PSA responses here, cohort A, one cycle demonstrated in blue, and cohort B, with the second cohort receiving two cycles of lutetium demonstrated in yellow. And many of these patients had PSA responses. There were a few that had PSA rises during treatment, but all of these patients went to prostatectomy and pelvic node dissection. And what they showed is that the majority of folks had some PSA response, and their primary endpoint of absorbed radiation dose was quite high. This is an initial study, a small cohort treated pre-surgery that is, I think, promising for thinking about what PSMA lutetium could potentially do in earlier disease, particularly for high-risk localized disease.

All right, so some early takeaways from our end. I think staging of high-risk localized prostate cancer has evolved certainly to include PSMA PET scans, so we should be doing them in our practices. We are seeing early detection of PSMA avid disease outside of the prostate, and I think adding AR-targeted therapies based on the STAMPEDE data should be standard of care in high-risk localized prostate cancer when there's disease outside of the prostate. And these interesting early trials like LuTectomy can inform our neoadjuvant approaches prior to surgery.

Elena Castro: Thank you, Tian. Indeed, this is a very interesting case, and we see these cases in the clinic everywhere. We are implementing PSMA tests for patients with high-risk disease, but sometimes we don't have enough evidence yet to decide how to treat these patients because, based on the STAMPEDE data as you presented, we should be offering these patients intensified treatment with abiraterone, perhaps when the ATLAS trial runs out. We may offer them apalutamide for a two-year period. But what if the PSMA PET is positive? Should we consider these patients metastatic and then treat them forever until they progress? Or, to me, this is something that sometimes I don't really know what to do. We discuss this a lot in my MDT. Is this also the case for you, or what do you do?

Tian Zhang: Absolutely. I think it poses a bit of a quandary because it's PSMA avid disease that's not quite metastatic on conventional imaging, and it is what we call a data-free zone where there's not a lot of definitive prospective trials. Certainly, trials are ongoing, such as in our cooperative groups, there's a trial called INDICATE that's really based on PSMA PETs in biochemical recurrence.

But in the upfront setting, it's a bit of a challenge to define, is this truly metastatic disease? And I would argue it may be accurate, but it's still an early phase of metastatic disease and certainly not meeting the criteria that would've enrolled patients, for example, to CHAARTED or to TITAN or ENZAMET. And so it's really hard to take these patients and say they absolutely need treatment until disease progression. In particular, for my practice, in the patients who have a really good response and they're two years in and their PSAs are undetectable, I think it's reasonable to have a discussion about treatment discontinuation. And this is more of a patient-based, case-by-case shared decision-making opportunity for our patients to tell us what they prefer. When we don't have the evidence to support one way or another, it's good for them to help us make that decision together.

Elena Castro: Yeah, my other concern is that we may not be offering radical treatment to these patients based on this PSMA PET spread that we don't see on conventional imaging, and perhaps they also may still benefit from radiation therapy or surgery. I entirely agree with you that this is something that should be discussed with the patients and for sure we need more data, more research, and more clinical trials.

Tian Zhang: Yeah, I absolutely agree with that. Elena, I don't think we should throw out the many decades of evidence for radiation to the primary tumor just because we've identified PSMA avid disease. And definitive treatment, I think, when the tumor burden, majority of it is in the primary, is still important. And I do agree that these patients should be receiving their localized treatment just as they had previously.

Elena Castro: Thank you, Tian, and thank you all for watching this new episode. Thank you.