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

## TL;DR

This study finds that starting treatment earlier in prostate cancer patients with specific PSA levels improves outcomes.

## Contribution

The study identifies optimal timing for treatment initiation in non-metastatic castration-resistant prostate cancer using PSA levels and doubling time.

## Key findings

- Patients with PSADT ≤ 10 months had worse metastasis-free survival compared to those with PSADT > 10 months.
- Starting treatment at lower PSA levels was linked to longer PSA progression-free survival.
- PSADT estimation was stable at PSA ≥ 0.5 ng/mL.

## Abstract

In non-metastatic castration-resistant prostate cancer, the optimal timing of treatment initiation is unclear, particularly the reliability of prostate-specific antigen doubling time (PSADT) at low prostate-specific antigen (PSA) levels and the effect of baseline PSA at treatment start on outcomes. We aimed to evaluate whether earlier use of novel androgen receptor pathway inhibitors (ARPIs) is beneficial by using PSA at initiation and PSADT. We found that patients with PSADT ≤ 10 months developed metastasis more often, and starting treatment at lower PSA was linked to longer prostate-specific antigen progression-free survival. Estimation of PSADT was stable when calculated at PSA ≥ 0.5 ng/mL. These findings support earlier ARPI initiation to optimize outcomes in high-risk nmCRPC.

Background: 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. Methods: We retrospectively analyzed 129 consecutive nmCRPC patients between 2000 and 2023. All patients were divided by PSADT ≤ 10 months (n = 109) or >10 months (n = 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. Results: Patients with PSADT ≤ 10 months had worse MFS than patients with PSADT > 10 months (4-year: 71.9% vs. 100%; p = 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; p < 0.001). In multivariate analysis, prior definitive local therapy (Hazard Ratio [HR] 0.409, p < 0.001), ARPIs as first-line treatment (HR 0.421, p < 0.001) and lower baseline PSA at treatment initiation (HR 0.961, p = 0.004) were significantly predictive factors for PSA-PFS. PSADT estimation remained accurate when calculated from PSA nadir values ≥0.5 ng/mL. Conclusions: 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.