Introduction: The most impactful prognostic factors in prostate cancer (PCa) involve Gleason Score (GS), preoperative Prostatic Specific Antigen (pPSA) and TNM stage. Elevated PSA levels have long been associated with poorer outcomes. However, High grade (HG) PCa, defined by GS ≥8, can occasionally present with low pPSA (<5 ng/ml). Recent evidence suggests that in HG PCa, lower pPSA levels may correlate with worse outcomes compared to intermediate levels, challenging the linear relationship between pPSA and PCa severity. This study aims to investigate whether low pPSA levels predict inferior recurrence-free survival and development of lethal PCa post-radical prostatectomy (RP) compared to intermediate pPSA levels in localized HG PCa patients. 

Methods: This retrospective cohort study analyzed patients with localized PCa and biopsy-proven HG who underwent RP at our center and PROCURE’s biobank between 2011 and 2021. Pathological data from prostate biopsies and surgical specimens were collected, and clinical outcomes were assessed. Statistical analyses were conducted using SAS 9.4 software. Restricted cubic spline with Cox regression, and Kaplan Meier analysis with log-rank tests were used to compare outcomes among patients with low (<5 ng/mL), intermediate (5-8 ng/mL) and high pPSA (>8 ng/mL) levels. Primary outcome was progression to lethal PCa defined as metastatic disease or PCa-related death. 

Results: A total of 729 patients were analyzed, with a median pPSA level of 7.3 ng/ml and a mean follow-up of 72 months. Pathologic evaluation revealed positive surgical margins in 373 (51%), ≥pT3 in 484 (66%) and pN1 in 175 (24%). Over the study period, biochemical recurrence occurred in 425 (58%), while 115 (16%) developed metastasis and 78 (11%) castration-resistant cancer. No significant statistical difference was observed in progression to lethal PCa between patients with low and intermediate pPSA levels. Restricted cubic spline with Cox regression revealed a direct correlation between PSA and lethal PCa. 

Conclusion: In our specific population of high-grade prostate cancer patients treated with radical prostatectomy, we did not observe a worse impact of low preoperative PSA levels compared to intermediate PSA levels on the progression to lethal PCa, contrary to findings from other studies.