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.

Data extraction

We asked a large language model to extract the following data columns from each paper:

• Study Design:

  • Study type (RCT, cohort, meta-analysis, etc.)
  • Comparison method (direct head-to-head, indirect comparison, network meta-analysis)
  • Sample size for each treatment arm
  • Follow-up duration
  • Risk of bias assessment or quality rating if provided

• Patient Population:

  • Cancer stage (metastatic vs non-metastatic prostate cancer)
  • Castration status (castration-resistant, hormone-sensitive)
  • Prior treatments received (chemotherapy, radiation, other AR inhibitors)
  • Risk stratification if provided (high-risk, intermediate-risk, low-risk)
  • Key demographic characteristics (age, performance status)

• Comparative Interventions:

  • Specific drugs compared (enzalutamide, abiraterone acetate, cabazitaxel, other AR inhibitors)
  • Dosing regimen and administration route
  • Combination treatments
  • Treatment duration
  • Concurrent therapies (ADT continuation, supportive care)

• Treatment Context:

  • Line of therapy (first-line, second-line, post-docetaxel)
  • Previous AR pathway inhibitor exposure and treatment duration
  • Reason for treatment change
  • Time since prior treatment discontinuation
  • Concurrent treatments like radiotherapy

• Effectiveness Outcomes:

  • Overall survival (median, hazard ratios, confidence intervals, p-values)
  • Progression-free survival (radiographic PFS, clinical PFS)
  • PSA response rates and time to PSA progression
  • Biochemical failure-free survival
  • Objective tumor response rates

• Safety Outcomes:

  • Overall adverse event rates (any grade, grade 3-5)
  • Specific adverse events mentioned (fatigue, cognitive impairment, hypertension)
  • Treatment discontinuation rates due to adverse events

• Key Findings:

  • Which treatment was superior for which outcomes
  • Magnitude of benefit
  • Authors’ recommendations for clinical practice

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.

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.

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 compared to switching to an alternative AR inhibitor.

Safety and Tolerability

Overall adverse event rates showed considerable variation across studies. In the cabazitaxel comparison, grade 3 or higher adverse events occurred in a significant proportion receiving cabazitaxel versus AR pathway inhibitors.

Synthesis

The apparent contradictions in comparative efficacy between enzalutamide and abiraterone can be reconciled by examining context-specific factors. The superiority of enzalutamide appears most consistent in mCRPC populations, while safety profiles show important distinctions that should guide treatment selection.

Conclusion

Enzalutamide appears to provide modest PFS benefits over abiraterone in certain populations without clear overall survival advantage. Sequencing from abiraterone to enzalutamide may offer better treatment options going forward. Key factors such as treatment context and safety profiles significantly influence clinical decision-making.