Purpose/Objective(s): Most serum PSA circulates in complex with protease inhibitors, but 5%-45% does it as enzymatically inactive free PSA (fPSA). PSA produced from prostate cancer (PC) cells appears to escape proteolytic processing, resulting in a greater fraction of complexed PSA (e.g. lower fPSA). Based on this, fPSA ratio is commonly used as an adjunct marker to improve the accuracy of PSA for screening. Within the PSA range 4-10 ng/mL, a fPSA ratio higher than 0.15 correlates with lower risk of harbouring PC. Nonetheless, post treatment fPSA is rarely quantified, and its prognostic value after radical external beam radiotherapy (EBRT) remains unexplored.

Materials/Methods: Institutional databases were queried to identify intermediate- and high-risk PC patients treated between 1992 and 2012 with EBRT, who had at least one ascertainment of fPSA during follow-up. Patients were stratified according to a fPSA cut-off of 0.15. Multivariable Cox regression models were performed to determine the correlation of post-EBRT fPSA and clinical outcomes.

Results: A total of 355 patients were identified. Of these, 262 (73.8%) and 93 (26.2%) had a fPSA ratio<0.15 and ≥0.15, respectively. Mean age, pre-treatment total PSA, and clinical T-category were similar in both groups. However, patients with a fPSA ratio ≥0.15 had a higher biopsy Gleason score (GS), NCCN risk group, and were more often treated with combined EBRT and androgen deprivation therapy (ADT). Mean follow-up time was similar in both groups (109.5 months vs. 111.9 months, p=0.725). Biochemical recurrence (BCR) rate were similar in both groups (77.6% vs. 80.5%, p=0.58), as expected from the Institutional lab policy of ascertaining fPSA when total PSA is in the 4-10ng/mL range and therefore BCR most likely already established. However, the metastasis and castrate resistant prostate cancer (CRPC) rates were higher in the fPSA ≥0.15 group (41.3% vs. 21.5%, p<0.001, and 67.4% vs. 37.5%, p=0.002, respectively). Multivariable models demonstrated that along with higher GS, a fPSA fraction>=0.15 conferred a statistically significantly higher hazard ratio (HR) for metastasis (HR 2.027, 95% CI 1.28-3.21, p=0.003), and CRPC (HR 3.066, 95% CI 1.565-6.004, p=0.01).

Conclusion: This study suggests that a fPSA ratio>=0.15 in the setting of post curative-intent EBRT denotes a more aggressive disease, reflected in higher rates of metastasis and CRPC. Our findings suggest a reversal in the significance of fPSA ratio in the post treatment state, and a potential novel role for this widely available and low-cost biomarker.