enzalutamide

Overview

Enzalutamide is a second-generation androgen receptor (AR) antagonist that inhibits AR nuclear translocation and DNA binding. It is FDA-approved for metastatic castration-resistant prostate cancer (mCRPC) and metastatic hormone-sensitive prostate cancer.

Evidence in the corpus

  • AR-amplified MSK-PCa2 CRPC patient-derived organoid was exquisitely sensitive to enzalutamide (IC50 ~50 nM) in vitro and in CB17 SCID xenografts; organoid lines without AR amplification were resistant, supporting AR amplification as a predictive biomarker for enzalutamide response PMID:25201530
  • Combination enzalutamide + everolimus significantly enhanced tumor growth inhibition over enzalutamide alone in MSK-PCa2 (AR-amplified, PTEN-loss, PIK3R1-mutant) xenografts, providing preclinical rationale for combined AR + PI3K/mTOR pathway blockade in CRPC PMID:25201530
  • Enzalutamide pre-treatment context: AR-V7 splice variant was detectable at low ratios in most pre-enzalutamide mCRPC cases; recurrent AR hotspot W742C confers bicalutamide agonism; 89% of mCRPC patients harbored at least one actionable alteration relevant to AR-directed therapy PMID:26000489
  • Variable AR transcriptional output across PRAD subtypes implies subtype-stratified responses to AR-directed therapies; enzalutamide named alongside abiraterone as relevant for SPOP/FOXA1-mutant primary prostate tumors with highest AR output PMID:26544944
  • Long-term enzalutamide treatment of LNCaP cells induced CRPC-NE molecular features including SPDEF promoter methylation, providing in vitro evidence that AR-targeted therapy pressure drives neuroendocrine trans-differentiation PMID:26855148
  • CRPC-NE tumors with high NEPC classifier scores are predicted to be unlikely responders to further enzalutamide (or abiraterone) and may be candidates for platinum chemotherapy or co-targeting strategies PMID:26855148
  • Only 3 of 63 mCRPC men in the prad_fhcrc rapid-autopsy cohort had received enzalutamide; with such a small n the study could not assess whether this potent AR antagonist induces divergent inter-metastasis resistance patterns (AR amplification, AR ligand-binding-domain mutation, AR splice variants). PMID:26928463
  • AR F877L resistance mutation detected in an mCRPC patient progressing after 4 years on apalutamide (ARN-509) and also confers resistance to enzalutamide; identified via MSK-IMPACT sequencing PMID:28825054

Resistance mechanisms

  • Organoid lines without AR amplification (e.g. MSK-PCa1, MSK-PCa4) were resistant to enzalutamide, suggesting AR amplification is required for single-agent sensitivity in CRPC PMID:25201530
  • CRPC-NE lacks AR amplification/mutations that drive CRPC-Adeno; low AR signaling and absent AR alterations indicate these tumors are intrinsically resistant to enzalutamide PMID:26855148

Cancer types (linked)

  • PRAD — castration-resistant prostate cancer (CRPC); including neuroendocrine CRPC (CRPC-NE) as a resistant subtype emerging under therapy pressure PMID:26855148

Sources

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