PSA persistence in the PSMA PET era: reassessing a risk factor after radical prostatectomy

BACKGROUND AND PURPOSE: The association of prostate-specific antigen (PSA) persistence after radical prostatectomy (RP) with inferior prognosis was demonstrated in a systematic review. However, all patients in the included studies lacked a prostate-specific membrane antigen Positron-Emissions-Tomography (PSMA-PET) before salvage radiotherapy (SRT). Since PSMA-PET has markedly improved sensitivity in detecting lymph node and distant metastases, it is unclear whether PSA persistence can be further considered a risk factor in patients or reflects an advanced tumor stage. MATERIALS AND METHODS: We used a retrospective database including 1222 PSMA-PET-staged prostate cancer patients treated with SRT for biochemical recurrence (BR) at 11 centers in five countries. After patients without information on PSA persistence were excluded, 1188 patients remained. The effects of PSA persistence and recurrence on overall survival (OS), metastasis-free survival (MFS), and biochemical progression-free survival (BPFS) were evaluated. RESULTS: The median follow-up time was 31.0 months (IQR range: 20.04-43.6 months). PSMA-PET revealed a higher incidence of local recurrence (43.5% vs. 30.0%, p = 0.01), and lower incidence of nodal failure in patients with PSA recurrence (40.6% vs. 30.5%, p < 0.001). In univariate analysis, patients with PSA recurrence had significantly superior 3-year biochemical progression-free survival (BPFS) (71.5% vs. 63.0%, p = 0.033) and MFS (83.0% vs. 78.0%, p = 0.049) compared with patients with PSA persistence. In the multivariate analysis, no significant differences were observed concerning BPFS (p = 0.738), MFS, (p = 0.826), or OS (p = 0.730). CONCLUSION: PSA persistence, traditionally considered a hallmark of a worse prognosis, may require reevaluation considering advances in imaging sensitivity. While our analysis does not definitively determine whether PSA persistence is no longer prognostic, it remains possible that its historically poorer prognosis and early focal detection via PSMA PET/CT have been therapeutically mitigated. As PSMA-PET becomes more widely available, its ability to detect hidden disease may help guide individualized treatment decisions.