BACKGROUND: Among men with high-risk non-metastatic castrate-resistant prostate 
cancer (nmCRPC), we used network meta-analysis to compare non-steroidal 
anti-androgens (NSAAs) and stratified class-level meta-analysis to identify 
subgroups with particular benefit from NSAAs with androgen deprivation therapy 
versus androgen deprivation therapy alone.
MATERIALS AND METHODS: We performed a systematic review of phase III 
parallel-group randomized controlled trials in adult men with nmCRPC. Primary 
outcome was metastasis-free survival (MFS). Secondary outcomes included overall 
survival (OS), prostate-specific antigen (PSA) progression-free survival (PFS), 
and rates of grade 3 to 4 adverse events (AEs). We assessed class-level effects 
using random effects models; effect modification owing to subgroup effects using 
random-effects models to pool study-level differences; and comparative outcomes 
between agents using fixed-effect network models in a Bayesian framework.
RESULTS: Three randomized controlled trials were identified. Pooled MFS, 
PSA-PFS, and OS were significantly greater with NSAA versus placebo (hazard 
ratio [HR], 0.32; 95% confidence interval [CI], 0.25-0.41; HR, 0.08; 95% CI, 
0.05-0.13; and HR, 0.74; 95% CI, 0.61-0.90, respectively). Subgroup analysis 
demonstrated a greater benefit with NSAAs in men with Eastern Cooperative 
Oncology Group performance status 0 (HR, 0.30; 95% CI, 0.24-0.38) versus 1 (HR, 
0.45; 95% CI, 0.36-0.56; P = .005), but no difference owing to PSA doubling time 
(P = .43) or use of osteoclast targeting therapy (P = .77). Bayesian analysis 
showed apalutamide and enzalutamide had a 56% and 44% likelihood of maximizing 
MFS, respectively, with subgroup analysis demonstrating these agents were 
preferred regardless of PSA doubling time and performance status. There was a 
44%, 41%, and 15% likelihood that apalutamide, darolutamide and enzalutamide 
offered the greatest OS benefit, respectively. Grade 3 to 4 AEs were more common 
with NSAAs (odds ratio [OR], 1.47; 95% CI, 1.27-1.71) and there was a 61% chance 
that darolutamide was preferred.
CONCLUSIONS: NSAAs improve survival in high-risk nmCRPC. Apalutamide and 
enzalutamide may result in improved oncologic outcomes. Darolutamide may result 
in fewer AEs. Phase IV data are needed to validate these findings.