# Comparative Efficacy of AR Inhibitors

## Comparative evidence: enzalutamide vs abiraterone or other AR pathway 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.

### Screening Criteria
- Population: Does the study include patients with prostate cancer receiving treatment with AR pathway inhibitors?
- Enzalutamide Intervention: Does the study include enzalutamide as one of the interventions being compared?
- AR Pathway Inhibitor Comparator: Does the study include abiraterone, apalutamide, darolutamide, or other AR pathway inhibitors as comparator(s)?
- Comparative Design: Does the study involve direct head-to-head comparison or indirect comparison through network meta-analysis?
- Comparative Outcomes: Does the study report at least one comparative outcome measure (efficacy, safety, or patient-reported outcomes)?
- Study Design: Is the study design a randomized controlled trial, cohort study, case-control study, systematic review, or meta-analysis?
- Comparison Groups: Does the study include comparison groups (i.e., is it NOT a single-arm study or case series without comparison groups)?

We considered all screening questions together and made a holistic judgment about whether to screen in each paper.

## 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 |
| S. Naqvi et al., 2025 | No | Network meta-analysis | 12,628 patients | Metastatic HSPC | Darolutamide vs abiraterone vs enzalutamide vs apalutamide | Not specified |
| G. Attard et al., 2021 | Yes | Meta-analysis of 2 RCTs | 1,974 (988 combination, 986 control) | High-risk nonmetastatic PC | Abiraterone+prednisolone vs abiraterone+prednisolone+enzalutamide vs ADT | 72 months median |
| M. Morris et al., 2019 | No | RCT | 1,311 (657 enzalutamide, 654 combination) | Metastatic CRPC | Enzalutamide vs enzalutamide+abiraterone+prednisone | Not specified |
| Xin Wang et al., 2020 | Yes | Meta-analysis | 3,546 patients | Metastatic CRPC | Abiraterone vs enzalutamide | Not specified |
| N. Sathianathen et al., 2020 | No | Network meta-analysis | Not specified | Metastatic HSPC | Docetaxel vs abiraterone vs enzalutamide vs apalutamide (all +ADT) | Not specified |
| B. Cao et al., 2023 | No | Systematic review and network meta-analysis | 14 RCTs | mCRPC, nmCRPC, mCSPC | Abiraterone vs apalutamide vs darolutamide vs enzalutamide | Not specified |
| Zhenheng Wei et al., 2021 | Yes | Meta-analysis | 5,199 (2,283 abiraterone, 2,916 enzalutamide) | Metastatic CRPC | Abiraterone vs enzalutamide | Not specified |

The studies varied considerably in treatment context. Two studies evaluated post-docetaxel mCRPC populations, while others examined first-line therapy in hormone-sensitive disease. Three studies were meta-analyses using indirect comparisons, while others were direct head-to-head RCTs. Disease settings ranged from metastatic CRPC to hormone-sensitive disease to high-risk nonmetastatic prostate cancer.

### 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).

When comparing sequencing strategies, the abiraterone-first followed by enzalutamide sequence showed numerically longer overall survival (28.8 months) compared to the reverse sequence (24.7 months), though this difference was not statistically significant (HR 0.79, 95% CI 0.54-1.16, p=0.23).

The combination of enzalutamide plus abiraterone did not improve overall survival compared to enzalutamide alone in metastatic CRPC, with median OS of 32.7 months versus 33.6 months (p=0.53). This finding indicates no additive survival benefit from combining these agents.

In high-risk nonmetastatic prostate cancer, combination therapy with abiraterone and prednisolone (with or without enzalutamide) significantly improved overall survival compared to ADT alone (HR 0.60, 95% CI 0.48-0.73, p<0.0001). Prostate cancer-specific survival was also improved (HR 0.49, 95% CI 0.37-0.65, p<0.0001).

### 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). Median clinical PFS was 4.4 versus 2.7 months (HR 0.52, 95% CI 0.40-0.68, p<0.001).

Enzalutamide demonstrated marked superiority over bicalutamide, with median PFS of 19.4 versus 5.7 months (HR 0.24, 95% CI 0.18-0.32, p<0.001). Radiographic PFS in metastatic patients also favored enzalutamide (HR 0.32, 95% CI 0.21-0.50, p<0.001).

### PSA Response and Biochemical Outcomes

PSA response rates demonstrated notable variation across comparisons. 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).

In the sequencing trial, first-line PSA response rates were 68% for abiraterone versus 82% for enzalutamide (p=0.023). On second-line therapy, enzalutamide demonstrated superior activity with 36% PSA response versus only 4% for abiraterone (p<0.0001).

### Safety and Tolerability

Overall adverse event rates showed considerable variation across studies. In the cabazitaxel comparison, grade 3 or higher adverse events occurred in 56.3% receiving cabazitaxel versus 52.4% receiving AR pathway inhibitors.

The enzalutamide plus abiraterone combination resulted in higher grade 3-5 adverse event rates (68.8%) compared to enzalutamide alone (55.6%), with higher treatment discontinuation rates (12% versus 5%).

### Key Findings

The apparent contradictions in comparative efficacy between enzalutamide and abiraterone can be reconciled by examining context-specific factors. Enzalutamide appears to offer modest PFS advantages over abiraterone in CRPC, particularly for biochemical and radiographic endpoints, without clear overall survival benefit. In hormone-sensitive disease, both agents show similar efficacy in most contexts, with potential enzalutamide advantage in low-volume settings. Sequencing from abiraterone to enzalutamide preserves more treatment options than the reverse order. Given similar overall efficacy and survival outcomes, treatment selection should weigh disease volume, prior therapies, sequencing strategy, toxicity profiles, and patient-specific factors including cardiovascular risk, concomitant medications, and functional status.

## References

1. [Xin Wang et al., (2020).](/content/review/5ac77594-d0bb-4495-a6d3-643732c2aca2/source/ss-227098871/index.html)
2. [R. de Wit et al., (2019).](/content/review/5ac77594-d0bb-4495-a6d3-643732c2aca2/source/ss-203607319/index.html)
3. [N. Sathianathen et al., (2020).](/content/review/5ac77594-d0bb-4495-a6d3-643732c2aca2/source/ss-207903186/index.html)
4. [B. Cao et al., (2023).](/content/review/5ac77594-d0bb-4495-a6d3-643732c2aca2/source/ss-256102903/index.html)
5. [Zhenheng Wei et al., (2021).](/content/review/5ac77594-d0bb-4495-a6d3-643732c2aca2/source/ss-237393420/index.html)
6. [D. Khalaf et al., (2019).](/content/review/5ac77594-d0bb-4495-a6d3-643732c2aca2/source/ss-208037345/index.html)
7. [D. Penson et al., (2016).](/content/review/5ac77594-d0bb-4495-a6d3-643732c2aca2/source/ss-207040881/index.html)
8. [S. Naqvi et al., (2025).](/content/review/5ac77594-d0bb-4495-a6d3-643732c2aca2/source/ss-276468111/index.html)
9. [G. Attard et al., (2021).](/content/review/5ac77594-d0bb-4495-a6d3-643732c2aca2/source/ss-245443315/index.html)
10. [M. Morris et al., (2019).](/content/review/5ac77594-d0bb-4495-a6d3-643732c2aca2/source/ss-190887000/index.html)