Association of Deep and Durable Prostate-specific Antigen Responses with Outcomes in Metastatic Hormone-sensitive Prostate Cancer: Insights from ARASENS and ARANOTE Trials

Prostate-specific antigen (PSA) is a critical biomarker in metastatic hormone-sensitive prostate cancer (mHSPC), offering insights into disease progression and treatment efficacy. An early PSA response to intensified therapy has significant prognostic implications; however, traditional methods often categorize PSA levels and focus on fixed time points, neglecting its dynamic nature. Joint models integrate longitudinal PSA trajectories and survival outcomes to provide a more comprehensive analysis. This study aims to evaluate the association between longitudinal PSA trajectories and overall survival (OS) in patients with mHSPC. We analyzed data from two phase 3 trials: ARASENS (n = 1305; androgen deprivation therapy [ADT] + docetaxel ± darolutamide) and ARANOTE (n = 669; ADT ± darolutamide). PSA trajectories were modeled using linear mixed models with restricted cubic splines, while OS was assessed using a Weibull model. Longitudinal PSA changes and OS were linked through joint modeling. In ARASENS, each doubling of the PSA decline rate was associated with a reduction in mortality rate of 29% (hazard ratio [HR] 0.71, 95% confidence interval [CI]: 0.69, 0.74); in ARANOTE, the reduction was 25% (HR 0.75, 95% CI: 0.72, 0.78). Higher baseline PSA levels and sharper postnadir increases were linked to worse outcomes. Darolutamide-treated patients showed favorable PSA trajectories, marked by steeper declines, prolonged nadirs, and slower increases, translating into improved OS. Limitations include interim OS data in ARANOTE and influence of prior treatments on baseline PSA. Joint modeling demonstrates a strong association between PSA dynamics and OS, underscoring darolutamide's potential to positively influence PSA trajectories and improve survival in mHSPC.