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Rashid Sayyid: Hello, everyone, and thank you for joining us for this UroToday, AUA Guidelines recording. I'm Rashid Sayyid, a urologic oncology fellow at the University of Toronto, along with Zach Klaassen, associate professor and program director at WellStar MCG Health. We'll be going over the recently amended AUA guidelines discussing advanced prostate cancer. This will be a six-part series recording. In the previous recording, we discussed the advanced prostate cancer epidemiology, as well as the diagnosis and evaluation. In this recording, we'll be going over a unique disease space, the biochemically recurrent without metastatic disease after the exhaustion of local treatment options. Just by way of reminder, this guideline was recently published in 2023, and this amendment was led by Dr. Michael Cookson.

Without further ado, let's delve into this disease space. The AUA guidelines statement regarding prognosis states that clinicians should inform patients with PSA recurrence after the exhaustion of local therapy regarding the risk of developing metastatic disease and follow these patients with serial PSA measurements and clinical evaluation. Clinicians may consider radiographic assessments based on overall PSA and PSA kinetics. This is a clinical principle. It's important to highlight that not all patients with biochemical recurrence are destined to experience clinical recurrence, metastatic disease, or cancer-related death. As such, there's a risk of overtreatment in this patient subgroup, and the AUA tries to give us some guidance with regards to who are the high-risk patients for metastatic disease and the subsequent prostate cancer mortality.


These high-risk patients following surgery are those with either a pathologic grade group four or five disease, or who have a PSA doubling time of one year or less. Then, conversely, those following radiotherapy, high-risk patients are those with a biopsy grade group four or five disease, as well as those with a short time to PSA failure, defined as 18 months or less. But, although these clinical characteristics give us guidance, they're not sufficient. So, the prognostic utility, meaning the discriminative accuracy of these factors, is quite limited. It's only about 67% for the prediction of metastasis and 69% for cancer-related death when patients are risk-stratified, meaning one or higher risk factors are high risk. So, when we consider that, at random, we can predict outcomes at 50%. We'll see that 67%, 69% is not that much higher, and clearly, there's a lot more left on the table, and we can do a better job with this.


Statement number five states that in patients with PSA recurrence after failure of local therapy who are at a higher risk for the development of metastases, for example, PSA doubling time less than 12 months, clinicians should perform periodic staging evaluations consisting of cross-sectional imaging, CT, MRI, and technetium bone scan, and/or preferably PSMA PET imaging. This is a clinical principle. So, although the PSMA PET imaging is included in this modification, the primary rationale for using conventional imaging is that the current standard of care systemic treatment options for metastatic hormone-sensitive patients are based on conventional imaging.


So, when you detect metastasis on PSMA PET currently, it's unclear how this fits in with the current treatment paradigm. As such, conventional imaging for now should be used as the imaging tool to guide treatment decisions. But it's also important to note that conventional imaging, as we know, has important limitations, particularly, at low PSA levels, meaning PSA less than five. It's estimated that conventional imaging will detect metastases in only 15% or 20%. Clearly, there's a lot of room for improvement in this space.


Statement number six, with regards to prognosis. This is a new addition. Clinicians should utilize PSMA PET imaging preferentially, where available, in patients with PSA recurrence after the failure of local therapy as an alternative to conventional imaging, due to its greater sensitivity, or in the setting of negative conventional imaging. This is an expert opinion, clearly, because we don't have evidence to inform why PSMA PET should be performed over these. Given that PSMA PET-guided therapy has yet to be proven to be superior to conventional imaging-directed therapy at this point.


Currently, we have two PET modalities that are FDA-approved in the biochemical recurrence setting. We have the 18 Fluorine fluciclovine or the Axumin PET scan, which has for the most part fallen out of favor but remains approved, and we have the PSMA PET/CT, which a lot of our listeners are familiar with. There are two tracers approved for PSMA PET, and these are the 68 Gallium PSMA 11, and 18F-DCFPyL or Pylarify. Let's start with 18 Fluorine fluciclovine or Axumin. The fluciclovine, it's an 18 Fluorine labeled analog of L-leucine that is selectively taken up by amino acid transporters that are upregulated on the surface of prostate cancer cells. So, it has the advantage of limited renal uptake and no activity in the urinary tract, but it doesn't work as well as PSMA PET.


We'll go into more detail about that later. The detection of prostate bed recurrences and nodal metastases in the biochemical recurrence setting with PSA less than one remains quite subpar, so between 21% and 72%. It's really dependent upon PSA levels, PSA kinetics, and histologic grades. Really, the factors need to be in the imaging's favor for it to find the metastasis, if one is present. So, this is with regards to prostate bed recurrence and known metastases. Conversely, for bones, it appears to detect these lesions at a similar rate to bone scans. So, the major takeaway for this modality is that the low detection rate among patients with low PSAs is the major limitation. What about PSMA PETs? What is PSMA or prostate-specific membrane antigen? It's a transmembrane protein that is expressed by the prostate, but also by proximal tubules, the salivary glands, and the small bowel.


But, the expression is upregulated in prostate cancer cells by a 1000-fold. The PSMA gene is located in the short arm of chromosome 11 in a region that's not commonly deleted in prostate cancer, although we do see that it is deleted in heavily pretreated advanced MCRPC and obviously with dedifferentiation and neuroendocrine differentiation. But, for the most part, it's highly prevalent in all forms of prostate cancer, including CRPC. A question that we hear often is, "Well, why does this work better than previous PSMA-targeted imaging modalities?" ProstaScint is one notable example. The major difference is really in three things. The current PSMA PET/CT radiotracers, they target the extracellular component, whereas ProstaScint targets intracellular, they have improved imaging characteristics compared to 111In radionuclide labeling. Then, it has a longer blood pool biodistribution for the antibody imaging agent, which allows for improved uptake and then expression. So, these characteristics overall help improve upon earlier generations of PSMA-targeted imaging.


We have two options, which work best. There are a lot of studies that have looked at these head-to-head. But one of the most notable ones is by Dr. Jeremie Calais, et al. It was published in Lancet Oncol in 2019. This was an open-label single-arm trial of 50 patients with biochemical recurrence following surgery and with low serum PSA levels between 0.2 and 2. Patients underwent both imaging modalities. They used the gallium tracer and obviously the Axumin PET scan within 15 days. All scans were interpreted by three blinded readers. The PET scan outperformed Axumin PET/CT with an overall detection rate of 56% versus 26%. We can see that here in the bar graph in the first pair of columns. Where's the majority of this discrepancy coming from? It's mainly differences in detection for pelvic lymph nodes, 30% versus 8%, and any extra-pelvic metastatic disease, 16% versus 0%.


Well, another question is, "Well, is this really just PSA-level dependent? Can I use Axumin PET scan at higher PSA level and assume that they're equivalent?" Not quite. If we look at the following, it is quite clear that the PSMA PET outperforms Axumin at PSA levels between 0.2-0.5, 0.5 to 1.0, and then 1.0 to 2.0. At any level, it works better, and often by three to four-fold. Another advantage is that it's easier to read. So, the inter-reader agreement was superior for the PSMA PET with kappa concordance values of 0.6 compared to the fluciclovine, which was less than 0.2. So, clearly a major difference. Many reasons to favor the gallium PET in this setting. Next, Fendler et al., JAMA Oncology 2019, published the results of a single-arm trial of 635 patients with biochemical recurrence following surgery, radiotherapy, or both, essentially trying to look at the performance of PSMA PET in the biochemical recurrence setting by PSA value.


So we see the PET detection rates, as expected, go up as the PSA levels go up. It appears that the inflection point, per se, is about one. We see that between 0.5 and 0.9, it is 57%, and then higher than one, it becomes 84%, 86%, and then 97%. This is really important when we counsel patients; there's often anxiety from our patients wanting earlier PSMA PETs in order to have PSMA-directed therapy earlier. First of all, we don't even know if that helps, but second of all, at very low PSA levels, such as 0.2 or less, the detection rate is not ideal. So, sometimes there may be some value in being prudent and waiting until at least the PSA value is 0.5 in order to improve the yield of the test.


Obviously, we're going to detect metastases at lower levels, but at higher levels, we will not. But overall, these are important figures to remember: at 0.5 or less, it's about 40%, and then 0.5 to 1.0, 57%; then, higher than 1.0, essentially, it's higher than 80%. This is a very important study with very informative data for counseling our patients.


Next, we had the CONDOR trial, which now looked at a different tracer, which is the Pylarify. So, the CONDOR trial is a Phase III trial of the 18 fluorine DCFPyL PET/CT in biochemically recurrent patients following surgery and/or radiotherapy who had negative or equivocal conventional imaging, which included Axumin and choline PET/CT. This is answering a different question: is there any value for PSMA PET in patients with negative or equivocal conventional imaging, including Axumin? So, we quite clearly see here in the graphs below that we have detection rates that improve as the PSA goes up. But, even at low PSA levels, those with negative or equivocal convention imaging, over a third, have evidence of metastasis on the PSMA PET. This goes up again to about 50% between 0.5 and 1.0, 2/3 between 1.0 and 2.0, and then 85% and 97% at higher PSA values. Clearly, there is value in doing the PSMA PET in patients with negative or equivocal conventional imaging.


Now I touched upon this before, but what is the major limitation of PSMA PET imaging? While we know that the findings on PSMA PET influences treatment decisions, and it was 64% in the CONDOR trial, to date, there's no proven survival benefit with PSMA PET/CT-directed approaches. But the community has recognized this limitation. There are numerous ongoing trials in this space, and there are too many to highlight. One of the notable ones is the PATRON trial, which is the PSMA PET/CT-guided intensification of therapy in patients at risk of advanced prostate cancer. This is a pragmatic phase III randomized trial. In brief, patients with prostate cancer at an elevated risk of metastases in the biochemically recurrent setting are randomized to either a PSMA PET with a PSMA PET-guided intervention versus just conventional limiting.


This isn't a question of getting PSMA PET in both and then directing or not directing treatment. One group gets a PSMA PET and the other group does not. This is a very practical approach to looking at the benefit of PSMA PET in this setting. We await the results of this trial and many others, and it'll be very exciting to see what this yields in the next two to three years. At this point, I'll turn it over to Zach to go over the remaining statements, beginning with the treatment of patients in this space.


Zach Klaassen: Thanks so much, Rashid. As Rashid mentioned, we'll talk about treatment. This is a very hot area of discussion, and we'll go through some of the historic trials, as well as some new data that has been published over the last few months. Statement seven says that, based on a clinical principle, for patients with a rising PSA after the failure of local therapy and no metastatic disease by imaging, clinicians should offer observation or clinical trial enrollment. This is based on a recommendation from two large observational studies that failed to demonstrate an overall survival benefit for immediate versus delayed ADT at the time of the development of metastatic disease. The panel does acknowledge, though, that there may be an overall survival benefit to early salvage ADT in patients with short PSA doubling times of less than nine months. Statement number eight suggests that, based on expert opinion, ADT should not be routinely initiated in this population.

However, if ADT is initiated in the absence of metastatic disease, intermittent ADT may be offered in lieu of continuous ADT. Let's talk about several of these historic trials. This is the TOAD trial, looking at immediate versus delayed ADT. This is a phase III RCT of 293 patients with PSA relapse following local therapy or not suitable for curative therapy based on their age or comorbidities. Patients were randomized 1:1 to immediate ADT versus delayed ADT, with a recommended interval of two years unless clinically contraindicated. As we can see in the overall survival curve on the right, immediate ADT was associated with an improved five-year overall survival, 91% versus 86%. We can see here at five years, this is where these curves do start to split.


Let's talk about the PR.7 trial. This is intermittent versus continuous ADT, a phase III RCT in 1,386 patients with PSA greater than three, more than one year post-primary or salvage XRT for localized prostate cancer. The intermittent ADT for this trial was administered in eight-month cycles. At the end of each eight-month cycle, treatment was discontinued if there was no evidence of clinical disease progression. The PSA was less than four and did not increase more than one nanogram per milliliter. For this trial, and this is based on data from 2012, the PSA threshold to reinitiate the next cycle at ADT was set at 10. At a median follow-up of seven years, no difference in overall survival between intermittent and continuous ADT, because the hazard ratio was 1.01, with very overlapping curves here on the right side of the overall survival Kaplan-Meier curve. Intermittent ADT was associated with better scores for hot flashes, desire for sexual activity, and urinary symptoms compared with those receiving continuous therapy.


Now, fast-forward to 2023, and we have the EMBARK trial. This is enzalutamide in high-risk non-metastatic biochemical recurrence prostate cancer. You can see the population for this trial on the left, which had to have a screening PSA greater than one after radical prostatectomy and at least two nanograms per milliliter above the nadir for primary external beam radiotherapy. These were high-risk patients, with a PSA doubling time less than or equal to nine months. No metastases on bone scan or CT/MRI. This is conventional imaging, which had to have a testosterone greater than 150, and prior hormonal therapy greater than nine months prior to radiotherapy, which was allowed. You can see the stratification factors at the bottom left of the screen. This is a one-to-one-to-one randomization to enzalutamide plus Lupron, placebo plus Lupron, or enzalutamide monotherapy. Then, basically, the patients were assessed for a PSA less than 0.2 at week 36.


If they were less than 0.2, the treatment was suspended, and monitoring of PSA was undertaken. Then, treatment was reinitiated if their PSA increased. If their PSA did not decrease to less than 0.2, they remained on treatment. We can see the primary endpoint, which we'll discuss in this presentation, was metastasis-free survival. At the top on the right, is metastasis-free survival for enzalutamide plus leuprolide versus leuprolide alone. On the bottom right, is metastasis-free survival for enzalutamide monotherapy versus leuprolide alone. We can see that both of these treatment arms versus leuprolide alone resulted in a statistically significant improvement in metastasis-free survival. For enza plus leuprolide, the hazard ratio was 0.42, with a 95% confidence interval of 0.30 to 0.61. For enzalutamide monotherapy alone versus leuprolide alone, the hazard ratio was 0.63, with a 95% confidence interval 0.46 to 0.87. Both of these treatments versus leuprolide alone resulted in improved metastasis-free survival after five years of follow-up.


But this did result in FDA approval in this disease space on November 16th, 2023. In conclusion, patients with a PSA increase after local therapy and a rapid PSA doubling time represent a high-risk population, not only for metastasis, but also for mortality. The use of PSMA PET/CT is transforming how we think about and manage these patients, and as Rashid alluded to, there are many trials ongoing to assess the benefit in terms of outcomes for PSMA PET/CT scans. As we just discussed, EMBARK was recently FDA-approved and provides a treatment option, either enzalutamide plus or minus ADT, for these high-risk patients with PSA doubling times less than nine months. We thank you very much for your attention. We hope you enjoyed this AUA Guideline discussion on behalf of UroToday.