Background: Darolutamide (DARO), a highly potent and structurally distinct androgen receptor inhibitor, prolonged metastasis-free survival by nearly 2 years and reduced the risk of death by 31% vs placebo (PBO) with a favorable tolerability profile in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) in ARAMIS. We present post-hoc analyses of ARAMIS to evaluate the association between metastatic progression with prostate-specific antigen (PSA) and clinical progression and to describe the distribution of metastatic progression between groups. Methods: Pts with nmCRPC were randomized 2:1 to DARO (n=955) or PBO (n=554) while continuing androgen-deprivation therapy. Descriptive analyses were performed using the primary data cutoff (Sept 3, 2018) for the double-blind period. Post-baseline metastases were based on central review of conventional radiographic imaging every 16 weeks. PSA and pain progression were defined per primary analysis (N Engl J Med. 2019;380:1235-46). Results: Metastatic progression was observed in 13.6% of DARO and 28.5% of PBO pts. Most pts had isolated progression as bone (DARO 46%, PBO 39%) or lymph node (32%; 40%) metastasis (Table). Pts with radiographic progression had shorter median time from initial diagnosis to study treatment (DARO 72.9, PBO 74.4 months) vs the overall ARAMIS population (86.2, 84.2 months). Of all pts with metastatic progression, baseline PSA levels (ng/mL) were similar in DARO (12.6) and PBO pts (15.1); DARO pts had lower median PSA before metastasis (16.7) vs PBO pts (48.0) and median absolute/relative PSA decrease from baseline of -0.7/-3.2% vs an increase for PBO pts of 29.5/181%. PSA progression before metastasis was observed in 55.6% (160/288) of pts, occurring in fewer DARO (45.4%) vs PBO pts (63.9%) (treatment difference 18.5%; nominal 95% CI 6.5%–30.6%). The median time between PSA progression and metastasis was 7.0 months with DARO vs 5.6 months with PBO. Pain progression before metastatic progression was rare and similar between groups (DARO 16.9%, PBO 17.7%). Conclusions: DARO significantly reduced risk of metastatic progression and improved overall survival vs PBO without changing the pattern of metastatic progression. Many pts with nmCRPC experienced metastatic progression without PSA progression, and pain progression was rare. These results support the use of imaging with PSA monitoring to properly identify disease progression in pts with nmCRPC. Clinical trial information: TBC.

^aPost-baseline. ^bLymph nodes ± bone ± visceral and/or soft tissue, including 9 DARO and 4 PBO pts with exclusive visceral and/or soft tissue progression.