The efficacy and adverse events of conventional and second-generation androgen receptor inhibitors for castration-resistant prostate cancer: A network meta-analysis

The study addresses whether second-generation androgen receptor inhibitors (enzalutamide, apalutamide, darolutamide) provide superior efficacy and acceptable safety compared with the conventional ARI bicalutamide in castration-resistant prostate cancer (CRPC). Given the development of resistance to androgen deprivation therapy (ADT) through mechanisms such as AR amplification, splice variants, and point mutations, second-generation ARIs have become standard options. However, head-to-head comparisons between conventional and second-generation ARIs and among second-generation ARIs are limited. The purpose is to indirectly compare efficacy (PFS, PSA-PFS, OS, MFS, PSA response) and AEs across these agents to inform clinical decision-making in nmCRPC and mCRPC.

Prior evidence indicates that conventional ARIs (e.g., bicalutamide) have limited long-term benefit in CRPC and may not improve overall survival. Bicalutamide can develop agonist properties with prolonged ADT exposure. Second-generation AR pathway inhibitors include abiraterone (androgen biosynthesis inhibitor) and ARIs (enzalutamide, apalutamide, darolutamide). Previous meta-analyses largely focused on nmCRPC and suggested darolutamide may have fewer grade ≥3 AEs and discontinuations, but did not include mCRPC populations for enzalutamide or apalutamide. Preclinical data suggest potent AR antagonism by darolutamide with low blood-brain barrier penetration, potentially reducing CNS AEs. This study expands on prior work by comparing both efficacy and safety across bicalutamide and three second-generation ARIs in both nmCRPC and mCRPC.

Design: Systematic review and Bayesian network meta-analysis following PRISMA guidelines (registered in PROSPERO: CRD42022370842). Data Sources: PubMed, Embase, and Cochrane Library searched from inception to October 1, 2022. Study Selection: Published RCTs of CRPC patients without prior chemotherapy receiving background ADT, randomized to bicalutamide, enzalutamide, apalutamide, darolutamide, or placebo. Outcomes: Efficacy endpoints included progression-free survival (PFS), PSA progression-free survival (PSA-PFS), overall survival (OS), metastasis-free survival (MFS), PSA response rate, and time to cytotoxic chemotherapy. Safety endpoints included overall AEs, grade ≥3 AEs, serious AEs (SAEs), AE-related discontinuation, AE-related mortality, fatigue, hypertension, and quality-of-life (FACT) degradation. Subgroups: Analyses stratified by nmCRPC and mCRPC for PFS and PSA-PFS. Data Extraction and Quality Assessment: Two reviewers independently extracted study and patient characteristics and assessed risk of bias using the Cochrane ROB tool; discrepancies were resolved by discussion or third reviewer. Statistical Analysis: Network meta-analyses were conducted using the Gemtc package in R under a Bayesian Markov chain Monte Carlo framework. Analyses used five chains with tuning iterations of 10,000, simulation iterations of 5,000, and thinning interval of 10. Hazard ratios (HRs) with 95% confidence intervals (CIs) were synthesized; heterogeneity assessed via I2 determined choice of random- vs fixed-effects models. Rank probabilities and league tables were generated. Subgroup analyses for nmCRPC and mCRPC were performed as specified.

- Studies and participants: 7 RCTs; 6,993 participants (placebo n=2,458; bicalutamide n=389; enzalutamide n=2,385; apalutamide n=806; darolutamide n=955). - PSA-PFS vs placebo: bicalutamide HR 0.67 (0.52–0.86); enzalutamide HR 0.15 (0.14–0.17); apalutamide HR 0.06 (0.05–0.08); darolutamide HR 0.13 (0.11–0.16). Among second-generation ARIs, apalutamide showed the greatest benefit on PSA-PFS. - PFS vs placebo: bicalutamide HR 0.74 (0.58–0.93); enzalutamide HR 0.25 (0.22–0.28); apalutamide HR 0.29 (0.24–0.36); darolutamide HR 0.38 (0.32–0.45). Enzalutamide and apalutamide outperformed darolutamide. - MFS (bicalutamide not assessed): enzalutamide HR 0.29 (0.24–0.35); apalutamide HR 0.28 (0.23–0.24); darolutamide HR 0.41 (0.34–0.50). Enzalutamide and apalutamide improved MFS more than darolutamide (enzalutamide vs darolutamide HR 1.41 [1.08–1.85]; apalutamide vs darolutamide HR 1.47 [1.10–1.95]). - PSA response rate (bicalutamide not assessed): enzalutamide HR 6.44 (4.74–9.04); apalutamide HR 20.11 (15.69–27.04); darolutamide HR 41.17 (21.86–82.94), suggesting higher PSA response with darolutamide and apalutamide vs enzalutamide. - OS (bicalutamide not analyzed): second-generation ARIs provided similar OS benefit; specific comparative HRs not fully reported in text. - Overall AEs (bicalutamide not analyzed): enzalutamide HR 1.42 (1.22–1.64); apalutamide HR 1.43 (0.96–2.12); darolutamide HR 1.41 (1.00–1.98); no significant differences among second-generation ARIs. - Grade ≥3 AEs vs placebo: bicalutamide HR 1.16 (0.94–1.42); darolutamide HR 1.24 (1.00–1.57); enzalutamide HR 1.17 (1.07–1.29); apalutamide HR 1.32 (1.13–1.55). Apalutamide showed the highest relative increase. - SAEs vs placebo: bicalutamide and apalutamide showed no significant increase; enzalutamide HR 1.17 (1.04–1.32) and darolutamide HR 1.22 (1.01–1.50) slightly increased SAE risk. - AE-related discontinuation vs placebo: bicalutamide HR 0.86 (0.58–1.28); enzalutamide HR 1.05 (0.84–1.33); darolutamide HR 1.03 (0.74–1.46); apalutamide HR 1.51 (1.02–2.32) increased discontinuations. - AE-related mortality vs placebo: bicalutamide HR 0.86 (0.34–2.11); darolutamide HR 3.03 (0.38–85.13); apalutamide HR 6.73 (1.10–183.14); enzalutamide HR 1.49 (1.03–2.20). - Fatigue vs placebo: bicalutamide HR 1.24 (0.96–1.61); enzalutamide HR 1.69 (1.50–1.90); apalutamide HR 1.33 (1.07–1.66); darolutamide HR 1.39 (1.02–1.94). - Hypertension vs placebo: bicalutamide HR 1.16 (0.94–1.42); darolutamide HR 1.24 (1.00–1.57); enzalutamide HR 1.17 (1.07–1.29); apalutamide HR 1.32 (1.13–1.55). - Subgroups: - mCRPC: PFS improved with bicalutamide HR 0.59 (0.45–0.78) and enzalutamide HR 0.21 (0.17–0.25); PSA-PFS improved with enzalutamide HR 0.19 (0.17–0.22), but not significantly with bicalutamide HR 0.82 (0.61–1.08). - nmCRPC: PFS not improved with bicalutamide HR 1.20 (0.68–2.18); enzalutamide HR 0.29 (0.24–0.35), apalutamide HR 0.29 (0.24–0.36), darolutamide HR 0.38 (0.32–0.45) improved PFS. Enzalutamide and apalutamide outperformed darolutamide. PSA-PFS markedly improved with all second-generation ARIs vs bicalutamide.

The findings support the hypothesis that second-generation ARIs provide superior disease control compared with the conventional ARI bicalutamide in CRPC. Enzalutamide and apalutamide consistently showed greater improvements in PFS, PSA-PFS, and MFS than darolutamide, though OS benefits among the second-generation agents appeared similar. Safety profiles were broadly comparable across second-generation ARIs, but apalutamide was associated with relatively higher rates of grade ≥3 AEs, AE-related discontinuations, and AE-related mortality, while enzalutamide had higher risks of hypertension and fatigue. In subgroup analyses, enzalutamide was superior to bicalutamide in both nmCRPC and mCRPC, and in nmCRPC both enzalutamide and apalutamide showed greater PFS and PSA-PFS benefits than darolutamide. These results inform treatment selection by balancing slightly greater efficacy of enzalutamide/apalutamide against specific AE patterns, recognizing that all ARIs were generally well tolerated.

Second-generation ARIs (enzalutamide, apalutamide, darolutamide) are superior to the conventional ARI bicalutamide for CRPC. Enzalutamide and apalutamide show similar and slightly greater efficacy than darolutamide, whereas apalutamide may carry higher risks of key adverse outcomes; differences in vital AEs among second-generation ARIs were not statistically significant. All agents were generally well tolerated. Direct head-to-head RCTs are warranted to validate indirect comparisons and clarify comparative effectiveness and safety.

- Heterogeneity and potential bias from included RCTs with some unclear risk domains; outcome reporting bias possible. - Limited follow-up in several studies, with OS not observed in most trials. - Inability to assess network consistency due to lack of closed loops (“ring” structure) in comparisons. - Indirect comparisons across populations (e.g., inclusion of both nmCRPC and mCRPC for some agents) may confound cross-drug comparisons. - Some outcomes not reported for bicalutamide (e.g., OS, MFS), limiting direct comparisons. - Possible inconsistencies in reported metrics and CIs across sources; reliance on aggregated trial-level data.