The Impact of Early Modification of Upfront Androgen Receptor Signaling Inhibitors on Survival Outcomes in Metastatic Hormone-Sensitive Prostate Cancer.

[BACKGROUND] This study evaluates the impact of early modification of upfront androgen receptor signaling inhibitors (ARSI) on outcomes among patients with metastatic hormone-sensitive prostate cancer (mHSPC).

[METHODS] This retrospective, multicenter cohort study included 590 patients with mHSPC who received upfront ARSI combined with androgen deprivation therapy. All had a follow-up duration of ≥ 6 months. The impact of early modification of ARSI without progression on survival outcomes was analyzed. The inverse probability of treatment weighting (IPTW) was applied to adjust for confounding factors associated with survival outcomes, comparing patients who did and did not discontinue ARSI early.

[RESULTS] Upfront abiraterone acetate, apalutamide, and enzalutamide were used in 50.8%, 28.1%, and 21.0% of patients, respectively. The rates of withdrawal of the upfront ARSI and initial dose reduction were 21.2% and 6.1%, respectively. The highest withdrawal rate (33.1%) was with apalutamide, mainly due to adverse events (89.1%). Apalutamide use (odds ratio [OR] 2.39, 95% CI: 1.50-3.80) and a low-risk CHAARTED status (OR 1.84, 95% CI: 1.08-3.14) were identified as independent risk factors for early ARSI withdrawal. IPTW analysis revealed early ARSI withdrawal (within 6 months) significantly correlated with poor castration-resistant prostate cancer-free survival (CRPC-FS) (p = 0.004) and second progression-free survival (PFS2) (p = 0.035). However, it had no significant relationship with overall survival (p = 0.280).

[CONCLUSIONS] Early withdrawal of initial upfront ARSI was associated with poor CRPC-FS and PFS2 among mHSPC patients. Maximizing the effectiveness of first-line treatment requires optimal management of ARSI therapy.

[TRIAL REGISTRATION] jRCTs021180021.