Optimal Timing of Treatment Initiation in Non-Metastatic Castration-Resistant Prostate Cancer Based on PSA Level and Doubling Time for Prognostic Benefit

<b>Background:</b> To clarify the timing of treatment initiation for non-metastatic castration-resistant prostate cancer (nmCRPC), we investigated the impact of baseline prostate-specific antigen (PSA) at treatment initiation on outcomes, the stability of PSADT estimation at low PSA levels, and the prognostic significance of PSADT. <b>Methods:</b> We retrospectively analyzed 129 consecutive nmCRPC patients between 2000 and 2023. All patients were divided by PSADT ≤ 10 months (<i>n</i> = 109) or >10 months (<i>n</i> = 20). PSA progression-free survival (PSA-PFS) and metastasis-free survival (MFS) were assessed by the Kaplan-Meier method, with predictive factors analyzed using Cox proportional hazards modeling. PSA-PFS was further compared across baseline PSA subgroups (<3, 3-5, 5-10, >10 ng/mL) in the PSADT ≤ 10 months cohort. <b>Results:</b> Patients with PSADT ≤ 10 months had worse MFS than patients with PSADT > 10 months (4-year: 71.9% vs. 100%; <i>p</i> = 0.021). In the PSADT ≤ 10 months group, novel androgen receptor pathway inhibitor (ARPI) treatment significantly improved PSA-PFS compared to those who did not (median: 44.0 vs. 16.6 months; <i>p</i> < 0.001). In multivariate analysis, prior definitive local therapy (Hazard Ratio [HR] 0.409, <i>p</i> < 0.001), ARPIs as first-line treatment (HR 0.421, <i>p</i> < 0.001) and lower baseline PSA at treatment initiation (HR 0.961, <i>p</i> = 0.004) were significantly predictive factors for PSA-PFS. PSADT estimation remained accurate when calculated from PSA nadir values ≥0.5 ng/mL. <b>Conclusions:</b> In patients with nmCRPC with PSADT ≤ 10 months, early initiation of ARPIs at lower PSA levels was associated with improved PSA-PFS. PSADT stabilized at PSA levels of >0.5 ng/mL. These findings support earlier ARPI initiation to optimize outcomes in high-risk nmCRPC.