Elicit: Comparative Efficacy of AR Inhibitors

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).

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.

The search returned 200 total results from Elicit.

We retrieved 200 papers most relevant to the query for screening.

Screening

We screened in sources based on their abstracts that met the following 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 comparators?
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)?
Human Studies: Is this a human study (i.e., NOT an in vitro or animal study)?
Original Research: Is this original research with adequate data (i.e., NOT a conference abstract, editorial, letter, or commentary without original data)?

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

Data extraction

We asked a large language model to extract pertinent data from each paper regarding:

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)
Comparative Interventions:
- Specific drugs compared (enzalutamide, abiraterone acetate, cabazitaxel, other AR inhibitors)
- Dosing regimen and administration route
Treatment Context:
- Line of therapy (first-line, second-line, post-docetaxel, etc.)
Effectiveness Outcomes:
- Overall survival (median, hazard ratios, confidence intervals, p-values)
- Progression-free survival (radiographic PFS, clinical PFS)
Safety Outcomes:
- Overall adverse event rates (any grade, grade 3-5)
Key Findings:
- Which treatment was superior for which outcomes

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

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).

Meta-analyses comparing abiraterone and enzalutamide to placebo found similar overall survival benefits: abiraterone HR 0.69 (95% CI 0.60-0.80, p<0.00001) and enzalutamide HR 0.67 (95% CI 0.59-0.75, p<0.00001).

Progression-Free Survival

Progression-free survival outcomes varied substantially by disease setting and prior treatment.

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).

Safety and Tolerability

Overall adverse event rates showed considerable variation across studies. In high-risk nonmetastatic disease, grade 3 or higher adverse events occurred in 37% of patients receiving abiraterone and prednisolone versus 58% receiving the triple combination with enzalutamide.

Synthesis

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.