A Deep Prostate-specific Antigen Response to Darolutamide plus Androgen Deprivation Therapy Is Associated with Better Clinical Outcomes in the Phase 3 ARANOTE Trial in Patients with Metastatic Hormone-sensitive Prostate Cancer

Darolutamide plus androgen deprivation therapy (ADT) significantly improved radiological progression-free survival (rPFS) versus ADT in ARANOTE (NCT04736199). Here we report prostate-specific antigen (PSA) responses and their correlation with clinical outcomes. Patients with metastatic hormone-sensitive prostate cancer were randomized to darolutamide 600 mg twice daily or placebo plus ADT. The proportion of patients achieving undetectable PSA (<0.2 ng/ml) and ultra-low PSA (<0.02 ng/ml) were determined overall and by baseline PSA category. A post hoc analysis was conducted to identify any correlation of rPFS, overall survival (OS), time to metastatic castration-resistant prostate cancer (mCRPC), and time to PSA progression with PSA responses and baseline PSA using an unstratified Cox regression model. The rate of achievement of PSA <0.2 ng/ml and of PSA <0.02 ng/ml at any time was threefold greater (63% vs 18%) and fivefold greater (43% vs 7.8%), respectively, in the darolutamide arm versus the placebo arm, with a consistent effect across baseline PSA subgroups. Depending on baseline PSA, up to 88% of patients treated with darolutamide achieved undetectable PSA and up to 69% achieved ultra-low PSA. Achievement of PSA <0.2 ng/ml versus ≥0.2 ng/ml was associated with much better rPFS, OS, time to mCRPC, and PSA progression, with hazard ratios of 0.19 (95% confidence interval CI 0.13-0.27), 0.14 (95% CI 0.09-0.21), 0.16 (95% CI 0.12-0.23), and 0.08 (95% CI 0.05-0.12), respectively. Darolutamide resulted in deep and durable PSA responses, regardless of baseline PSA. A deep PSA response was associated with better clinical outcomes, and patients reaching ultra-low PSA had the greatest clinical benefits from darolutamide.