Upfront use of androgen receptor pathway inhibitor (ARPI) in combination with androgen deprivation therapy (ADT) has become standard care for metastatic hormone-sensitive prostate cancer (mHSPC), demonstrating significant prostate-specific antigen (PSA) responses and survival benefits. However, the feasibility and outcomes of ARPI deintensification, particularly in patients with good PSA response and cost considerations, remain unclear. We aimed to explore the deintensified PSA progression-free survival (dPSA-PFS) and predictive factors in patients with mHSPC who underwent deintensification from ARPI plus ADT to ADT monotherapy after achieving excellent PSA control.

We retrospectively included patients with de novo mHSPC treated with upfront ARPI plus ADT between 2018 and 2024, who underwent ARPI discontinuation in a PSA progression-free state due to non-clinical considerations. Deintensified PSA-PFS was defined as the interval from ARPI discontinuation to either PSA progression or re-initiation of ARPI/other second-line antineoplastic therapies. Predictive factors were evaluated by Kaplan–Meier analysis and Cox proportional hazards models.

A total of 30 patients were assessed, with a median follow-up of 48 months from diagnosis. The median PSA progression-free duration before ARPI discontinuation was 26 months. The median dPSA-PFS was not reached, while the 2-year dPSA-PFS rate was 77.1% (95% confidence interval [CI] 60.5-93.7). Undetectable PSA level at nadir was related to lower risk of dPSA progression (hazard ratio [HR] 0.077, 95% CI 0.007-0.805, p=0.032), and a higher 2-year dPSA-PFS rate (94.1% vs. 50.0%, p=0.007). Patients with more than 26 months of PSA progression-free status before ARPI discontinuation had a higher 2-year dPSA-PFS rate (92.9% vs. 60.6%, p=0.044), though this wasn’t statistically significant in multivariate analysis (p=0.106). Initial PSA level, age, Gleason score, bone metastases, and visceral metastasis were not significantly associated with dPSA-PFS.

In mHSPC patients who achieved an undetectable PSA nadir after approximately two years of ARPI plus ADT, subsequent treatment deintensification may be feasible and display sustained PSA control, though longer-term outcomes require further investigation.