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Christopher Wallis: Hello, and welcome to this UroToday Journal Club. Thanks again for joining us as we discuss this recent publication entitled Identifying the Best Candidates for PSMA PET/CT as the Primary Staging Approach Among Men with High-Risk Prostate Cancer and Negative Conventional Imaging. I'm Chris Wallis, a Fellow in Urologic Oncology at Vanderbilt, and with me today is Zach Klaassen, Assistant Professor in the Division of Urology at the Medical College of Georgia.

This is the recent publication in the European Association of Urology, with the citation here led by Dr. Kishan.

Prostate cancer imaging is a critical component in our care of these patients and forms an important part all throughout the natural history of the disease, from initial staging of patients at the time of their diagnosis prior to local therapy, to the detection of occurrence and monitoring of response to systemic therapy. We know that, from a huge amount of literature, conventional imaging performs quite poorly in identifying small volume distant disease, particularly when PSA levels are less than two nanograms per milliliter, however, novel PET/CT radiotracers may address this issue and increase our sensitivity for low volume disease.

The ProPSMA trial is perhaps the best evidence to support the idea of using these novel radiotracers in the original staging of patients prior to local therapy. And so this trial included men with untreated, biopsy-proven prostate cancer, who would be considered for curative-intent treatment. And they had to have a high-risk criterion as defined by PSA greater than 20, Gleason Grade Group three, four, or five, or clinical stage T3. Patients were then randomized to undergo conventional imaging with a bone scan and CT, or Gallium-PSMA PET. And there was crossover for patients who did not have evidence of a high volume metastases on their first imaging. And then the authors assessed the accuracy of these imaging approaches compared to the reference standard. As you can see here, comprising both hard and soft criteria.

And an assessment of their primary outcome, the authors found that PSMA PET/CT had 27% greater accuracy than conventional imaging.  Notably, this increase in accuracy was consistent across any metastatic disease, pelvic nodal disease, or distant metastases, including both the AUCs, as well as the specificity and sensitivity of the test modality. And overall, it is relatively uncommon to see tests that perform better in terms of both specificity and sensitivity at the same time.

More recently, we've seen data from the OSPREY trial, which examined the use of 18-fluoride-DCFPyL, which is a different PSMA radiotracer. And this study examined patients in two cohorts and potentially most relevant here is cohort A, which is patients who underwent PSMA-PET/CT prior to radical prostatectomy with pelvic lymphadenectomy. As you can see in the figure in the bottom right, PSMA-PET/CT diagnostic performance was quite high, considering particularly the specificity.

However, the question remains, how do we best employ these imaging approaches? And so it's worth noting that these trials enrolled patients with generally high-risk features. So, proPSMA, as we discussed, included patients with PSAs of 20 or greater, Gleason Grade Group three, four, or five disease, or clinical T3 or greater disease. Similarly, CONDOR included patients with PSAs of 20 or greater, Gleason score of eight or higher, that is Grade Group four, five, or a clinical-stage T3a or higher. And as the authors of this review note, according to NCCN criteria, Grade Group three, which was included in the proPSMA trial, is not inherently a high-risk patient in the absence of other high-risk features. And so we know that the risk of metastatic spread differs among included patients, and this study, therefore assessed who is most likely to benefit from the use of PSMA staging.

And so, to do so, they explored predictors of nodal and metastatic upstaging on patients who had NCCN-defined high-risk prostate cancer.

They used patients who were included in two prior prospective trials of PSMA PET/CT, where PSMA PET/CT was used as primary staging for patients with high-risk prostate cancer. And they excluded patients who had known non-regional lymph nodes or distant metastatic disease on the basis of conventional imaging, those who started ADT more than three months prior to their PET/CT, those with pre-existing prostate cancer treatments, those without a baseline CT, and those who had enlarged lymph nodes, according to their CT, which would, again, be keeping with the diagnosis of a distant disease according to conventional imaging.

The primary endpoint of interest was upstaging to nodal or metastatic involvement, and analysis included multivariable logistic regression, including initial PSA, Gleason grade group, percentage of positive cores, and clinical T stage. And the authors derived a nomogram for upstaging based on variables included in this regression model and then performed internal validation using 10-fold cross-validation of the area under the receiver operating characteristic curve.

Now I'm going to pass it over to Dr. Klaassen to walk us through the results of the study.

Zachary Klaassen: Thanks Chris. So this is the CONSORT diagram for the study. They assessed 558 patients for eligibility. Ultimately, 220 were deemed eligible and 213 were included in the analysis for upstaging. Overall, there were 51 patients that were upstaged, including 45 that were nodally upstaged, and 19 that had metastatic upstaging.

This table looks at the clinical and demographic characteristics. The median age for these patients was 68. You can see percent positive cores about 50/50 for greater than or equal to 50% or less than 50%. Median PSA was 11.9. The most common Gleason grade group was Gleason grade group five at 41.3%, followed by Gleason grade group four at 40.8%. The most common clinical T stage was one at 58.2%. And in terms of conventional imaging breakdown, you can see here that 47.9% of patients had a CT of the abdomen/pelvis, 59.6% had a bone scan, and 86.4% of patients had an MRI. The median number of biopsy cores was 12 and the median number of positive cores was five.

This is the analysis of overall upstaging looking at the multivariable model. And you can see here that, in bold on the right, the p values for percent positive cores and Gleason grade group were both significant, for upstaging percent positive cores with an odds ratio of 1.03, and a 95% confidence interval of 1.01 to 1.04, and Gleason grade group, the odds ratio of 2.15, and a 95% confidence interval of 1.33 to 3.45.

This figure looks at the characteristics of patients undergoing nodal and metastatic upstaging by percent positive core and Gleason grade group. The left figure looks at the percent positive core, and you can see on the right part of this figure, greater than 50% percent positive core, at a 33% rate of upstaging compared to 15% percent positive core less than 50%. Looking at the middle figure, this is Gleason grade group, on the right of this figure is Gleason grade group five, with a 33.0% overall upstaging rate for that Gleason group five, and for Gleason group less than five, a 17.6% upstaging rate. On the far right figure, this combines the percent positive core and the Gleason group. On the very far right, the percent positive core greater than 50% and patients with a Gleason grade group five biopsy, 40.4% upstaging rate, compared to 34.2 for Gleason group four. If we look at the less than 50% percent positive core, Gleason group 5, 24.4% upstaging rate.

This is the ROC curve showing the sensitivity and specificity trade-off for different cutpoints and the overall discrimination of the model. And you can see here that this is an area under the curve of 0.75 and a 95% confidence interval for this model of 0.67 to 0.83.

This is the decision curve analysis demonstrating the net benefit associated with PSMA PET/CT use for overall upstaging. And looking at this decision curve analysis, when using a cutpoint of 0.45, which corresponds to a 22% overall upstaging risk, 90% of patients whose risk falls below this cutoff can be safely spared from a PSMA PET/CT study.

This is the final nomogram for predicting the probability of overall upstaging by PSMA PET. The top line is the points used for the nomogram. At the bottom is the probability of overall upstaging. And based on the multivariable model and the previous figures, the percent positive core was one of the main components of this nomogram as well as the Gleason grade group.

So, several discussion points from this study. The percent positive core is a powerful predictor of increased nodal metastatic and any upstaging. And this study also confirms the predictive value of Gleason Group for upstaging. Patients with high-risk disease may benefit from elective nodal radiotherapy if receiving definitive radiation, and the use of advanced systemic therapy agents. And it is likely that early metastatic failures that we do see after definitive-intent treatment for high-grade prostate cancer may reflect occult metastases at the time of the initial treatment.

So, in conclusion, the findings from this study indicate that percent positive cores and Gleason Group are highly predictive of upstaging by PSMA PET/CT, for patients with high-risk prostate cancer. Patients with percent positive cores greater than or equal to 50% and Gleason Group four, five disease will benefit most from PSMA PET/CT as part of their staging, and also benefit from therapeutic intensification strategies aimed at extraprostatic disease. And finally, further studies should validate the importance of these prognostic variables and identify whether changes in treatment lead to better outcomes.

Thank you very much, and we hope you enjoyed this UroToday Journal Club looking at PSMA PET/CT for staging high-risk prostate cancer.