How to Manage Patients with PSA Persistence Following Radical Prostatectomy? "Presentation" Derya Tilki
November 15, 2024
At the 2024 Advanced Prostate Cancer Consensus Conference (APCCC), Derya Tilki analyzes PSA persistence after radical prostatectomy, examining its prevalence, correlation with adverse outcomes, and role of PSMA PET/CT and genomic testing. She discusses current treatments and ongoing trials exploring intensification strategies for high-risk patients.
Biographies:
Derya Tilki, MD, Associate Professor of Urology, Martini-Klinik Prostate Cancer Center, Hamburg, Germany
Biographies:
Derya Tilki, MD, Associate Professor of Urology, Martini-Klinik Prostate Cancer Center, Hamburg, Germany
Read the Full Video Transcript
Derya Tilki: Good afternoon. First of all, I would like to thank the organizers, Silke and Aurelius, for this kind invitation to the beautiful Lugano and for the opportunity to talk about how to manage patients with PSA persistence following radical prostatectomy. These are my disclosures.
Between 5% and 30% of men continue to have detectable PSA after radical prostatectomy, which may result from undetected micrometastatic disease, malignant residual disease in the surgical bed, or residual benign tissue at surgical margins.
In the majority of studies, which were mostly retrospective, persistent PSA is defined as detectable post-radical prostatectomy PSA of above 0.1 within four to eight weeks. Only a few studies have looked at detectable PSA of above 0.03.
With regards to imaging, Maia and colleagues have looked at 150 patients with persistent PSA, and at a median PSA value of 0.6, 67% had PSMA-positive lesions. Fifty-nine percent had lesions outside the prostatic fossa, and 39% had evidence of distant metastasis.
The current EAU guidelines recommend offering PSMA PET/CT to men with a persistent PSA above 0.2 if the results will influence subsequent treatment decisions.
This is a study from our department with about 11,600 patients. 8.8% harbored persistent PSA, and clearly patients with persistent PSA, as seen here, have worse outcomes when compared to undetectable PSA. At 15 years after radical prostatectomy, metastasis-free survival was 53% versus 93%.
In multivariable analysis, higher PSA, more advanced pathologic tumor stage, Grade Group 3 to 5, positive surgical margins, and positive lymph nodes were associated with an increased risk for persistent PSA. And persistent PSA is not only a surrogate for advanced disease and pathology, but in multivariable analysis predicts metastasis and death after radical prostatectomy.
But a few of the patients with persistent PSA don't go on to progression, and one may argue that the reason for these patients having persistent PSA could be benign prostatic glands at surgical margins of the specimen. And Shah and colleagues looked at this in a cohort of 119 patients where 11% had benign glands on the surgical margin, mostly patients with larger prostate. What the authors found is that the benign glands were most often at the apex and also most often only focal. Therefore, concluding that the presence of benign glands at the surgical margins likely is a rare cause of an elevated PSA level after radical prostatectomy.
This is a systematic review by Ploussard and colleagues on persistently elevated PSA. Twenty-five studies were included in the systematic review, and as mentioned, PSA persistence was, in this systematic review, also significantly correlated with disease aggressiveness and associated with worse oncological outcomes when compared to patients with undetectable PSA levels. Recurrence-free survival rates varied from 22% to 67%.
The authors also looked at results from subgroup analysis of randomized controlled trials to confirm the worse prognostic value of persistent PSA. For example, the RTOG 9601 randomizing salvage radiotherapy plus placebo versus salvage radiotherapy plus bicalutamide, or the German ARO trial and the EORTC trial, looking at immediate radiotherapy versus observation. All of these trials have confirmed that persistent PSA is significantly associated with poorer overall survival. The North American SWOG trial has looked at the subgroup of patients with persistent PSA, and also confirmed that there's a significant benefit from immediate radiotherapy in this subgroup.
This is a study by Dan Spratt and colleagues, multi-institutional, 477 men. They evaluated if a 22-gene genomic classifier, in this case Decipher, can independently predict development of metastasis in men with PSA persistence postoperatively. We have heard about this test this morning. Also, it looks at 22 genes across seven cancer pathways and gives a score between zero and one of genomic risk of metastasis, with a score above 0.6 being high risk.
What the authors found is that on multivariable analysis only genomic high risk, persistent PSA, and lymph node invasion remained prognostic factors for metastasis, and that among detectable PSA patients, the five-year metastasis rate was below 1% for genomic low and intermediate risk, and 18% for genomic high risk. Also, when looking at persistent PSA patients only, the authors found that genomic high risk remained independently prognostic on multivariable analysis.
What about salvage radiotherapy plus minus ADT in patients with PSA persistence? This is a randomized trial from France. Results were presented at ASTRO 2022, but there is no full publication available yet. Looking at patients with persistent PSA between 0.2 and 2 and randomizing patients to immediate salvage radiotherapy versus immediate salvage radiotherapy plus concomitant ADT. And what the authors had presented at ASTRO was that the median event-free survival was not reached in both arms. They stated that with 53 events, the probability that the addition of ADT to salvage radiotherapy is actually better than salvage radiotherapy is 79%.
The EAU guidelines recommend treating men with no evidence of metastatic disease and with persistent PSA with salvage radiotherapy and additional hormonal therapy.
These are ongoing trials in this space. Most of the trials look at patients with biochemical recurrence and include patients with persistent PSA. For example, the NRG-GU006 and 008 look at the addition of apalutamide to salvage radiotherapy. The FORMULA-509 study looked at salvage radiotherapy and six months of ADT with or without abiraterone and apalutamide post-radical prostatectomy. And this study also included patients with persistent PSA. Data were presented at ASCO-GU 2023, full publication not available yet, and have suggested that there's a benefit for the combination therapy.
The RTOG 3506 looks at the addition of enzalutamide to salvage radiotherapy and is one of the very rare studies which exclusively look at patients with persistent PSA—meaning there was never a postoperative undetectable value—as is the NRG-GU002 study randomizing patients to salvage radiotherapy plus ADT with or without docetaxel.
So in conclusion, PSA persistence is strongly and independently correlated with adverse pathology and poorer survival outcomes. Risk stratification according to pathological features, PSA levels and kinetics, and genomic classifiers may aid in personalization of treatment. Current evidence for guiding the management is, however, low, and patients with persistent PSA have clearly worse outcomes, need to be monitored much more closely, and treated more aggressively than patients who had an undetectable PSA after radical prostatectomy, then developed biochemical recurrence. We have seen that trials of treatment intensification are ongoing.
Thank you.
Derya Tilki: Good afternoon. First of all, I would like to thank the organizers, Silke and Aurelius, for this kind invitation to the beautiful Lugano and for the opportunity to talk about how to manage patients with PSA persistence following radical prostatectomy. These are my disclosures.
Between 5% and 30% of men continue to have detectable PSA after radical prostatectomy, which may result from undetected micrometastatic disease, malignant residual disease in the surgical bed, or residual benign tissue at surgical margins.
In the majority of studies, which were mostly retrospective, persistent PSA is defined as detectable post-radical prostatectomy PSA of above 0.1 within four to eight weeks. Only a few studies have looked at detectable PSA of above 0.03.
With regards to imaging, Maia and colleagues have looked at 150 patients with persistent PSA, and at a median PSA value of 0.6, 67% had PSMA-positive lesions. Fifty-nine percent had lesions outside the prostatic fossa, and 39% had evidence of distant metastasis.
The current EAU guidelines recommend offering PSMA PET/CT to men with a persistent PSA above 0.2 if the results will influence subsequent treatment decisions.
This is a study from our department with about 11,600 patients. 8.8% harbored persistent PSA, and clearly patients with persistent PSA, as seen here, have worse outcomes when compared to undetectable PSA. At 15 years after radical prostatectomy, metastasis-free survival was 53% versus 93%.
In multivariable analysis, higher PSA, more advanced pathologic tumor stage, Grade Group 3 to 5, positive surgical margins, and positive lymph nodes were associated with an increased risk for persistent PSA. And persistent PSA is not only a surrogate for advanced disease and pathology, but in multivariable analysis predicts metastasis and death after radical prostatectomy.
But a few of the patients with persistent PSA don't go on to progression, and one may argue that the reason for these patients having persistent PSA could be benign prostatic glands at surgical margins of the specimen. And Shah and colleagues looked at this in a cohort of 119 patients where 11% had benign glands on the surgical margin, mostly patients with larger prostate. What the authors found is that the benign glands were most often at the apex and also most often only focal. Therefore, concluding that the presence of benign glands at the surgical margins likely is a rare cause of an elevated PSA level after radical prostatectomy.
This is a systematic review by Ploussard and colleagues on persistently elevated PSA. Twenty-five studies were included in the systematic review, and as mentioned, PSA persistence was, in this systematic review, also significantly correlated with disease aggressiveness and associated with worse oncological outcomes when compared to patients with undetectable PSA levels. Recurrence-free survival rates varied from 22% to 67%.
The authors also looked at results from subgroup analysis of randomized controlled trials to confirm the worse prognostic value of persistent PSA. For example, the RTOG 9601 randomizing salvage radiotherapy plus placebo versus salvage radiotherapy plus bicalutamide, or the German ARO trial and the EORTC trial, looking at immediate radiotherapy versus observation. All of these trials have confirmed that persistent PSA is significantly associated with poorer overall survival. The North American SWOG trial has looked at the subgroup of patients with persistent PSA, and also confirmed that there's a significant benefit from immediate radiotherapy in this subgroup.
This is a study by Dan Spratt and colleagues, multi-institutional, 477 men. They evaluated if a 22-gene genomic classifier, in this case Decipher, can independently predict development of metastasis in men with PSA persistence postoperatively. We have heard about this test this morning. Also, it looks at 22 genes across seven cancer pathways and gives a score between zero and one of genomic risk of metastasis, with a score above 0.6 being high risk.
What the authors found is that on multivariable analysis only genomic high risk, persistent PSA, and lymph node invasion remained prognostic factors for metastasis, and that among detectable PSA patients, the five-year metastasis rate was below 1% for genomic low and intermediate risk, and 18% for genomic high risk. Also, when looking at persistent PSA patients only, the authors found that genomic high risk remained independently prognostic on multivariable analysis.
What about salvage radiotherapy plus minus ADT in patients with PSA persistence? This is a randomized trial from France. Results were presented at ASTRO 2022, but there is no full publication available yet. Looking at patients with persistent PSA between 0.2 and 2 and randomizing patients to immediate salvage radiotherapy versus immediate salvage radiotherapy plus concomitant ADT. And what the authors had presented at ASTRO was that the median event-free survival was not reached in both arms. They stated that with 53 events, the probability that the addition of ADT to salvage radiotherapy is actually better than salvage radiotherapy is 79%.
The EAU guidelines recommend treating men with no evidence of metastatic disease and with persistent PSA with salvage radiotherapy and additional hormonal therapy.
These are ongoing trials in this space. Most of the trials look at patients with biochemical recurrence and include patients with persistent PSA. For example, the NRG-GU006 and 008 look at the addition of apalutamide to salvage radiotherapy. The FORMULA-509 study looked at salvage radiotherapy and six months of ADT with or without abiraterone and apalutamide post-radical prostatectomy. And this study also included patients with persistent PSA. Data were presented at ASCO-GU 2023, full publication not available yet, and have suggested that there's a benefit for the combination therapy.
The RTOG 3506 looks at the addition of enzalutamide to salvage radiotherapy and is one of the very rare studies which exclusively look at patients with persistent PSA—meaning there was never a postoperative undetectable value—as is the NRG-GU002 study randomizing patients to salvage radiotherapy plus ADT with or without docetaxel.
So in conclusion, PSA persistence is strongly and independently correlated with adverse pathology and poorer survival outcomes. Risk stratification according to pathological features, PSA levels and kinetics, and genomic classifiers may aid in personalization of treatment. Current evidence for guiding the management is, however, low, and patients with persistent PSA have clearly worse outcomes, need to be monitored much more closely, and treated more aggressively than patients who had an undetectable PSA after radical prostatectomy, then developed biochemical recurrence. We have seen that trials of treatment intensification are ongoing.
Thank you.