5100 Background: The treatment landscape for metastatic castration-sensitive prostate cancer (mCSPC) has changed substantially with the adoption of early treatment intensification using androgen-receptor pathway inhibitors (ARPI) and chemotherapy, in addition to traditional androgen deprivation therapy (ADT). PSA nadir has long been used to support prognosis and inform treatment decisions; however, the historical thresholds were established based on patients treated solely with ADT and may not fully reflect outcomes in the modern era of combination therapy. Although emerging evidence suggests that a PSA nadir of < 0.2 ng/dl is associated with improved disease control and survival, a systematic evaluation across available mCSPC trials is needed to clarify the prognostic value of PSA nadir and its potential role in guiding treatment decisions. Methods: A systematic search of PubMed, Cochrane Library, and ClinicalTrials.gov was conducted through October 31, 2025, to identify studies reporting outcomes by PSA nadir category in men with mCSPC. Eligible studies included patients initiating systemic therapy with ADT alone or in combination with ARPI and/or chemotherapy. The reported hazard ratios (HR) for time-to-event endpoints stratified by PSA nadir (=< 0.2 ng/dl) were analyzed to get pooled HR. The primary outcome was overall survival (OS). Results: A total of eight trials comprising 6,582 patients were included. The pooled HR for the primary endpoint, overall survival (OS), was 0.27 (95% CI: 0.21–0.36; I² = 88.1%), indicating a clinically meaningful survival advantage among patients achieving PSA nadir. Consistent findings were observed for secondary outcomes. Achieving a PSA nadir ≤0.2 ng/mL was associated with longer radiographic progression-free survival (HR 0.23; 95% CI: 0.12–0.45; I² = 87.8%) and longer PSA progression-free survival (HR 0.19; 95% CI: 0.08–0.45; I² = 92.6%). A PSA nadir ≤0.2 ng/mL also correlated with a delayed onset of castration resistance (HR 0.31; 95% CI: 0.16–0.61; I² = 93.5%). Assessment of publication bias using Begg’s and Egger’s tests revealed no significant evidence of small-study effects for any endpoint. Conclusions: Across contemporary mCSPC trials, achieving a PSA nadir of ≤0.2 ng/mL consistently predicts improved survival and delayed disease progression. These findings establish PSA nadir as a clinically meaningful and cost-effective biomarker that can help guide treatment-intensification and de-intensification strategies in routine practice. Study Hazard Ratio (HR) 95% Confidence Interval (CI) Weight (%) SWOG9346 0.23 0.19, 0.27 13.80 SWOG S0925 0.20 0.14, 0.28 12.06 ARASENS 0.49 0.37, 0.65 12.65 CHAARTED 0.41 0.32, 0.53 13.00 ARCHES 0.24 0.17, 0.34 11.82 TITAN 0.35 0.25, 0.48 12.09 ARANOTE 0.14 0.09, 0.21 10.79 SWOG S1216 0.25 0.21, 0.30 13.78 Overall (Pooled) 0.27 0.21, 0.36 100.00
Avudaiappan et al. (Wed,) studied this question.