Elicit: Comparative Efficacy of AR Inhibitors
Comparative Efficacy of AR Inhibitors
Comparative evidence: enzalutamide vs abiraterone or other AR pathway inhibitors
Abstract
Ten studies including direct randomized trials, crossover studies, and network meta-analyses compared AR pathway inhibitors across metastatic castration-resistant, hormone-sensitive, and high-risk nonmetastatic prostate cancer settings. In metastatic CRPC, indirect comparisons found no significant overall survival difference between enzalutamide and abiraterone (HR 1.03, 95% CI 0.854-1.242), though enzalutamide demonstrated superior radiographic progression-free survival (HR 0.516, 95% CI 0.438-0.608), time to PSA progression (HR 0.365, 95% CI 0.303-0.441), and PSA response rates (RR 0.69, 95% CI 0.61-0.79, p<0.00001). Sequencing order materially affects outcomes: abiraterone followed by enzalutamide achieved longer time to second progression (19.3 versus 15.2 months, HR 0.66, p=0.036) than the reverse sequence, driven by markedly asymmetric second-line activity (36% PSA response for enzalutamide post-abiraterone versus 4% for abiraterone post-enzalutamide). Combining enzalutamide with abiraterone provided no survival benefit over enzalutamide alone (median OS 32.7 versus 33.6 months, p=0.53) while increasing grade 3-5 toxicity (68.8% versus 55.6%). In hormone-sensitive disease, network meta-analysis found no significant differences between ARPi agents in most contexts, though enzalutamide showed advantage in low-volume disease. Safety profiles were broadly similar, though enzalutamide ranked most toxic for hypertension across disease settings and increased fatigue risk (RR 0.45, 95% CI 0.24-0.85). The evidence supports similar overall survival with modest enzalutamide advantages for progression endpoints in CRPC, favors abiraterone-first sequencing, and suggests treatment selection should consider disease volume, sequencing strategy, and toxicity profiles rather than efficacy differences alone.
Methods
We analyzed 10 sources from an initial pool of 200, using 9 screening criteria. Each paper was reviewed for 7 key aspects that mattered most to the research question.
Results
Characteristics of Included Studies
The systematic review included 10 studies comparing AR pathway inhibitors in prostate cancer across different disease settings and lines of therapy.
| Study | Full text retrieved? | Study Type | Sample Size | Disease Setting | Comparison | Follow-up |
|---|---|---|---|---|---|---|
| R. de Wit et al., 2019 | No | RCT | 255 (129 cabazitaxel, 126 ARPi) | Metastatic CRPC | Cabazitaxel vs abiraterone/enzalutamide | 9.2 months median |
| D. Khalaf et al., 2019 | Yes | RCT (crossover) | 202 (101 per arm) | Metastatic CRPC | Abiraterone→enzalutamide vs enzalutamide→abiraterone | 22.8 months median |
| D. Penson et al., 2016 | Yes | RCT | 396 (198 per arm) | Nonmetastatic/metastatic CRPC | Enzalutamide vs bicalutamide | Not specified |
| ... | ... | ... | ... | ... | ... | ... |
Overall Survival
Overall survival data showed variable results across different disease contexts and treatment lines. In metastatic CRPC patients previously treated with docetaxel, cabazitaxel demonstrated superior overall survival compared to switching to an alternative AR pathway inhibitor, with median OS of 13.6 versus 11.0 months (HR 0.64, 95% CI 0.46-0.89, p=0.008).
Progression-Free Survival
Progression-free survival outcomes varied substantially by disease setting and prior treatment. In post-docetaxel mCRPC, cabazitaxel achieved superior imaging-based PFS (median 8.0 months) compared to switching to an alternative AR inhibitor (3.7 months), with HR 0.54 (95% CI 0.40-0.73, p<0.001).
PSA Response and Biochemical Outcomes
Cabazitaxel achieved 35.7% PSA response versus 13.5% for AR pathway inhibitors (p<0.001). Enzalutamide showed substantially higher response rates than bicalutamide: 81% versus 31% for ≥50% PSA decline (p<0.001).
Safety and Tolerability
Overall adverse event rates showed considerable variation across studies. The enzalutamide plus abiraterone combination resulted in higher grade 3-5 adverse event rates (68.8%) compared to enzalutamide alone (55.6%).
Synthesis
The apparent contradictions in comparative efficacy between enzalutamide and abiraterone can be reconciled by examining context-specific factors. The superiority of enzalutamide over abiraterone for certain endpoints appears most consistent in mCRPC populations.
Treatment Context and Sequencing Effects: The sequencing order materially affects cumulative treatment benefit.
Combination Strategy Failures: The combination of enzalutamide plus abiraterone did not improve outcomes compared to enzalutamide alone.