Comparative efficacy of AR Inhibitors

Enzalutamide and abiraterone provide similar overall survival in prostate cancer, but enzalutamide shows modest advantages for progression endpoints in castration-resistant disease, and sequencing from abiraterone to enzalutamide yields better outcomes than the reverse order due to preserved second-line activity.

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.

Records from Elicit search

n = 200

Papers screened using:

• Population
• Enzalutamide Intervention
• AR Pathway Inhibitor Comparator
• Comparative Design
• Comparative Outcomes
• Study Design
• Comparison Groups
• Human Studies
• Original Research

n = 200

Papers screened out

n = 190

Papers included for extraction

n = 10

Paper search

We performed a semantic search across over 138 million academic papers from the Elicit search engine, which includes all of Semantic Scholar and OpenAlex.

Search query

“Comparative evidence: enzalutamide vs abiraterone or other AR pathway inhibitors”

Returned 200 total results from Elicit.

Retrieved 200 papers most relevant to the query for screening.

Screening

Criteria

• Population: Patients with prostate cancer receiving AR pathway inhibitors?
• Enzalutamide Intervention: Study includes enzalutamide as one of the interventions?
• AR Pathway Inhibitor Comparator: Study compares to abiraterone, apalutamide, darolutamide, or other AR pathway inhibitors?
• Comparative Design: Direct head-to-head comparison or indirect comparison?
• Comparative Outcomes: At least one comparative outcome measure reported?
• Study Design: Randomized controlled trial, cohort study, etc.?
• Comparison Groups: Comparison groups for studies?
• Human Studies: Is this a human study?
• Original Research: Is this original research?

Considered all questions together and made a holistic judgement.

Data extraction

Study Design

• Extract study design and methodological characteristics for comparative evidence between AR pathway inhibitors, including:
  • 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

• Extract patient population characteristics relevant to comparing AR pathway inhibitors, including:
  • Cancer stage
  • Castration status
  • Prior treatments received
  • Risk stratification
  • Key demographic characteristics

Comparative Interventions

• Extract details of the AR pathway inhibitors being compared.

Treatment Context

• Extract treatment line and sequencing information for AR pathway inhibitor comparisons.

Effectiveness Outcomes

• Overall survival, progression-free survival, PSA response rates, etc.

Safety Outcomes

• Extract safety and tolerability data comparing AR pathway inhibitors, including adverse events.

Key Findings

• Extract main conclusions and clinical implications for AR pathway inhibitor comparisons.

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.

The studies varied considerably in treatment context.

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.

PSA Response and Biochemical Outcomes

PSA response rates demonstrated notable variation across comparisons. Cabazitaxel achieved a higher PSA response versus AR pathway inhibitors.

Tumor Response

Objective tumor response rates were reported in limited studies.

Safety and Tolerability

Overall adverse event rates showed considerable variation across studies. Higher grade 3-5 adverse event rates with combined therapies compared to individual agents.

Synthesis

The apparent contradictions in comparative efficacy between enzalutamide and abiraterone can be reconciled by examining context-specific factors.

References

1. Xin Wang et al., (2020). Comparison of effectiveness and safety outcomes of abiraterone versus enzalutamide in patients with metastatic castration-resistant prostate cancer: a systematic review and meta-analysis. Journal of Pharmacy & Pharmaceutical Sciences.
2. R. de Wit et al., (2019). Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. New England Journal of Medicine.
3. N. Sathianathen et al., (2020). Indirect Comparisons of Efficacy between Combination Approaches in Metastatic Hormone-sensitive Prostate Cancer: A Systematic Review and Network Meta-analysis. European Urology.
4. B. Cao et al., (2023). Adverse Events and Androgen Receptor Signaling Inhibitors in the Treatment of Prostate Cancer: A Systematic Review and Multivariate Network Meta-analysis. European Urology Oncology.
5. Zhenheng Wei et al., (2021). Efficacy and Safety of Abiraterone Acetate and Enzalutamide for the Treatment of Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis. Frontiers in Oncology.