Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club discussion. Today, we're discussing a recent publication titled PSMA PET Validates Higher Rates of Metastatic Disease for EAU Biochemical Recurrence Risk Groups: An International Multicenter Study. I'm Chris Wallis, an Assistant Professor in the Division of Urology at the University of Toronto. Joining me today is Zach Klaassen, Assistant Professor in the Division of Urology at the Medical College of Georgia. This is a citation for this recent publication, and we'll jump right in here.

By way of background, we know that following curative intent treatment, either with radical prostatectomy or radiotherapy, approximately one in four men with prostate cancer have biochemical recurrence. Recent work, as highlighted here from the EAU Prostate Cancer Guidelines Panel, provides a risk scoring approach that can identify patients at higher risk of metastasis and progression.

You see in the table one there that both PSA doubling time, as well as Gleason score, are important in the risk of biochemical recurrence following a radical prostatectomy. When we look at those who have had initial radiotherapy, the interval from primary therapy to biochemical failure, as well as biopsy Gleason score, are important predictors.

In addition to biochemical recurrence, it's important to know that PSA persistence, whether it is a persistently identifiable PSA, following radical prostatectomy is a differing pattern, which has worse oncologic outcomes. While we rely heavily on PSA, PSMA or advanced prostate cancer related imaging may also provide important information. We know that across the spectrum of prostate cancer care imaging forms a critical component of our approach, from initial staging prior to treatment, detection of recurrence and monitoring a response to systemic therapy.

The use of novel radio tracers, such as PSMA, may have increased sensitivity for cancer detection and allow us to improve our diagnosis. As a result, PSMA-PET/CT is now included in EAU guidelines and is approved by the US FDA.

In this study, the authors sought to assess the disease extent on PSMA imaging according to risk groups, including the EAU biochemical recurrent high risk, EAU biochemical recurrence low risk, and biochemical persistence. In doing so, they sought to identify subgroups of men with undetectable disease on PSMA-PET/CT, local regional disease, or distant metastatic disease. To do this, they used a multi institutional cohort of patients who had a biochemical recurrence or biochemical persistence following curative intent treatment, and they used the standard definitions here. For biochemical recurrence, we looked at patients treated surgically who had a PSA of 0.2 or greater, and for those treated with radiotherapy who had a PSA of exceeding nadir plus two. This comprised nearly 1,600 men.

There was a second set of patients who had biochemical persistence, and this was just under 400 patients. These patients all underwent PSMA-PET in the context of prospective clinical trials. Patients had to have prostate adenocarcinoma with evidence of biochemical recurrence or persistence, as well as sufficient data for a risk stratification according to the EAU nomogram approach. Patients were excluded if they had known M1 disease, had received prior salvage therapy, or who had undergone PSMA-PET within three months after their initial treatment.

Their detailed imaging approach was performed according to local guidelines, but in general, encompassed whole body PET/CT from the skull to mid thigh. In general, while CT was used, MRI was sometimes used as the hybrid modality on the basis of availability or patient level contraindication to CT scanning. PSMA-PET findings were interpreted using the promised criteria. A multivariate binomial logistic regression model was assembled to assess the independent predictors of identification of M1 disease on PSMA imaging.

Now, going to hand it over Zach to walk us through the interesting results of this analysis.

Zachary Klaassen: Thank you, Chris. This is the study for flow chart for the study. As Chris mentioned, there was three trials that included patients in this analysis, as well as 183 retrospective patients. Overall, there was roughly 2,100 patients that had sufficient data, and 1,960 that were included in the final analysis.

This table looks at the patient characteristics and PSMA-PET stages. As you can see, there's a lot of information on this slide, which we'll walk through. Looking up at the top, the radiotherapy-treated patients are broken down by low risk and high risk. To the left of this is the radical prostatectomy patients, broken down by low risk, high risk and biochemical persistence. As we can see, looking at age, these are majority of men in their late sixties or early seventies.

When we look at PSA cutoffs, not surprisingly for the patients that underwent radical prostatectomy, there's more patients with a PSA of less than 0.5 and 0.5 to less than one compared to the radiotherapy patients. When we look at the PSAs of two to less than five and greater than five, the majority of these patient are in the radiotherapy group.

For PSMA doubling time for the radical prostatectomy, low risk patients it was 20 months, for high risk was 4.2 months, and for biochemical persistence was 4.5 months. And for radiotherapy, low risk was 8.5 months, and for high risk was 4.1 months. For Gleason score in the radical prostatectomy group, the low risk was primarily Gleason seven, and the high risk was also Gleason seven at 54%, and most commonly in biochemical persistence was Gleason seven at 43.5%. For the radiotherapy, low risk patients most commonly was Gleason seven at 68.6%, and for the high risk patients was 46.8%.

Looking at adjuvant radiotherapy after radical prostatectomy, the patients that had adjuvant radiotherapy in the low risk group was 28.4%, and the high risk group was 39.5%, and in the biochemical persistence group was 20.4%. When we look at the PSMA-PET stages, as Chris already outlined, we see that patients with no disease included 33% in the radical prostatectomy low risk, 29% in the high risk, and 22% in the biochemical persistence, compared to 6.5% for radiotherapy low risk patients, and 4.4% in high risk patients.

Where we see some deviation is in the M1 metastatic. In the radical prostatectomy, low risk patients was 24.4%, for high risk patients 36.7%, and for biochemical persistence was 39.9%. We see in the radiotherapy high risk patients, M1 disease up to 69.6%. Looking at M1 group, we see most commonly in the radical prostatectomy was M1B, which was also consistent in the radiotherapy low and high risk patients. Notably, M1C was highest at 9.5% in the radiotherapy biochemical recurrent high risk patients.

This is a very nice figure looking at PET disease extent in the EAU biochemical recurrent low high and bio biochemical persistent patients. This is basically a nice visual of what we just discussed on the previous table, and you can see that we focus on the EAU low risk patients. There was 32% that were M1, and 52% that were M0 local regional. When we look at the EAU high risk patients we're up to 42% M1, and 33% local regional, and in the biochemical persistent patients, looking actually quite similar to the EAU high risk patients, 40% of these patients were M1, and 38% were local regional.

This is a four spot looking at predictors of PET M1 disease. You can see here that there was no difference in initial therapy in terms of predicting M1 disease, whether the patients had prostatectomy or radiotherapy. When we look at the PSA going from less than 0.5 all the way up to greater than five, we see a treatment effect looking at the odds ratio of having an M1 disease. So for greater than 0.5 to one, odds ratio of 2.24, up to 3.17 for one to less than two, 5.56 for greater than two to five, and 12.16 for greater than five.

Looking at the risk groups, we see that the risk groups predict M1 disease very well. Compared to low risk patients, high risk patients had an odds ratio of 2.91, and biochemical persistence versus low risk disease had an odd ratio of 3.08.

There's several discussion points from this trial that are worth mentioning. As we know, the Ga-PSMA-11 and DCFPyL PET were recently approved by the FDA on the basis of high accuracy for prostate cancer staging. As we know, as well, the approval of PSMA-ligand PET is soon expected to enable broad availability for staging a biochemical recurrence or biochemical persistence.

These findings in this study present a detailed map of disease extent in the EAU BCR risk groups or biochemical persistence. The observed intra and intergroup heterogeneity in PET stage come with important implications for this EAU classification. First, PSMA PET stratified by biochemical risk or biochemical persistent groups into relevant subgroups with undetectable, locoregional, or distant metastatic disease. Of note, after radical prostatectomy, about one third of patients were stratified into each of these three subgroups with somewhat higher rates of metastatic disease in the BCR high risk or biochemical persistent patients.

Secondly, disease extent detected by PSMA PET was higher in post-radiotherapy patients than in radical prostatectomy patients. Post-radiotherapy, biochemical recurrent, low risk patients yield a PSMA PET M1 rate that is similar to the post-radical prostatectomy, high risk or biochemical persistent patients.

In conclusion, men with high risk biochemical recurrence, according to the EAU Prostate Cancer Guidelines Panel and biochemical persistence have high higher rates of metastatic disease. Discordant subgroups, including metastatic disease and low risk patients and no disease and high risk patients warrant the inclusion of PSMA PET stage to refine risk assessment.

We thank you very much for your attention. We hope you enjoyed this Uro Today Journal Club discussion.