Clinical significance of PSA dynamics in castration-sensitive prostate cancer treated with ARSI doublet therapy: A multicenter study.

Background: Androgen receptor signaling inhibitors (ARSIs) have revolutionized the treatment of metastatic castration-sensitive prostate cancer (mCSPC). Prostate-specific antigen (PSA) dynamics, including PSA nadir, PSA response rate, and time to PSA nadir (TTN), are well-established markers of disease control. We evaluated the clinical significance of these PSA dynamics using data from a multicenter clinical database for mCSPC patients.

Methods: We conducted a multicenter retrospective study including 552 mCSPC patients treated with ARSI and ADT, and 262 patients treated with combined androgen blockade (CAB). PSA nadir, PSA response rate, and TTN were evaluated using predefined cut-offs. Clinicopathological data were collected and subsequently analyzed using multivariate Cox regression models to investigate impact of the PSA dynamics on oncological outcomes, including castration resistant prostate cancer free survival (CRPCFS), cancer-specific survival (CSS), and overall survival (OS). Propensity score matching (PSM) was used to minimize selection bias and balance baseline characteristics between treatment the groups. The achievement rates of low PSA nadir and high PSA response were then evaluated.

Results: In the ARSI cohort, 36.4% of patients achieved a PSA nadir of ≤ 0.02 ng/mL, and 65.8% attained a PSA response rate of ≥ 99 %. Notably, patients with a PSA nadir of ≤ 0.02 ng/mL, a PSA response rate ≥ 99%, and TTN > 12 months demonstrated significantly improved oncological outcomes. Multivariate analyses confirmed that these PSA dynamics were independent predictors of favorable oncological outcomes. A PSA nadir of ≤ 0.02 ng/mL was as an independent predictor of improved oncological outcomes compared to a nadir of > 0.2 ng/mL (CRPCFS: HR, 0.063; CSS: HR, 0.12; OS: HR, 0.15; P < 0.001). A PSA response rate of ≥ 99% compared to < 95%, also independently predicted more favorable outcomes (CRPCFS: HR, 0.29; CSS: HR, 0.26; OS: HR, 0.30; P < 0.001). Furthermore, a TTN > 12 months was also an independent predictor of improved survival compared to TTN ≤ 3 months (CRPCFS: HR, 0.12; CSS: HR, 0.08; OS: HR, 0.12; P < 0.001). PSM with a 1:1 ratio was associated with significantly higher rates of PSA nadir ≤ 0.02 ng/mL and PSA response rate ≥ 99% in the ARSI doublet group compared to the CAB group.

Conclusions: Our study demonstrates that achieving a PSA nadir ≤ 0.02 ng/mL, a PSA response rate ≥ 99%, and a longer TTN are associated with significantly improved oncological outcomes. Furthermore, we elucidated how PSA dynamics differ between ARSI doublet therapy and CAB, highlighting the distinct characteristics of each. These findings provide valuable clinical information for guiding the management and prognosis of mCSPC in routine clinical practice.