enzalutamide

Overview

Enzalutamide is a second-generation nonsteroidal androgen receptor (AR) inhibitor approved for the treatment of prostate cancer across multiple disease stages, including metastatic castration-resistant prostate cancer (mCRPC), nonmetastatic castration-resistant prostate cancer (nmCRPC), and metastatic hormone-sensitive prostate cancer (mHSPC). Unlike earlier antiandrogens, enzalutamide inhibits androgen receptor signaling at multiple steps: it blocks ligand binding to the AR ligand-binding domain (LBD), prevents nuclear translocation of the receptor, and impairs AR binding to DNA. This multi-modal blockade confers substantially greater suppression of the AR signaling axis than first-generation agents. Enzalutamide's mechanism centers on its high-affinity binding to the AR LBD, an interaction that has served as the benchmark against which newer AR-targeting strategies — including AR transactivation domain inhibitors (AR-TAD inhibitors) — are measured.

Beyond its established role in prostate cancer, enzalutamide has attracted growing interest as a combination partner in oncology, given that AR signaling intersects with a range of resistance mechanisms, cell survival pathways, and tumor-biology phenomena including ferroptosis and lipid remodeling. Its deployment as a pharmacological probe in both clinical and preclinical settings has made it a central tool for understanding castration-resistant disease biology and for identifying co-vulnerabilities that can be exploited therapeutically.

Focus of Latest Publications

Recent publications continue to position enzalutamide as a central androgen receptor pathway inhibitor in advanced prostate cancer. In the Phase III Alliance A031201 trial context, circulating tumour DNA analyses examined the evolution of AR and non-AR alterations in metastatic prostate cancer treated with AR pathway inhibitors such as enzalutamide and abiraterone. This work reflects the ongoing effort to understand how tumors adapt under AR-directed pressure and how genomic changes in ctDNA may track resistance evolution.

Several studies focused specifically on enzalutamide resistance in castration-resistant prostate cancer. One report identified diminished expression of decorin as a driver of resistance by suppressing ACSL4-dependent lipid remodeling and ferroptosis, concluding that promoting DCN-mediated ferroptosis might enhance enzalutamide sensitivity in prostate cancer cells. Another study described an IGFBP3-SphK1/S1P signaling axis as a driver of resistance in advanced prostate cancer, reinforcing the idea that noncanonical survival pathways can undermine AR blockade. A separate investigation found that MECOM was overexpressed in both CRPC and enzalutamide-resistant CRPC and interacted with AR in the nucleus, supporting a role for AR-associated transcriptional reprogramming in treatment resistance.

Enzalutamide was also studied in combination regimens. A Phase II study compared 131I-LNTH-1095 radioligand therapy plus enzalutamide versus enzalutamide alone in men with PSMA-avid metastatic castration-resistant prostate cancer, indicating continued interest in combining AR inhibition with targeted radioligand approaches. Another Phase Ib clinical trial combined enzalutamide with the BCL-2 inhibitor venetoclax and reported reduced circulating tumor cells in responding patients, suggesting potential activity for dual targeting of AR signaling and apoptotic dependence. In a separate protocol, the RENAPCA Phase Ib trial was designed to evaluate neoadjuvant/adjuvant relugolix and enzalutamide in high-risk locally advanced prostate cancer, reflecting expansion of enzalutamide into earlier disease settings and combination endocrine strategies.

Clinical outcome studies also examined how disease progression manifests during enzalutamide therapy. One analysis characterized radiographic progression with and without PSA rise in patients treated with enzalutamide across metastatic hormone-sensitive prostate cancer and nonmetastatic castration-resistant prostate cancer, highlighting that radiographic progression may occur even without a concurrent PSA increase. Another report on the EMBARK trial secondary end points described enzalutamide monotherapy for high-risk biochemical recurrence, building on the phase 3 evidence base for this treatment approach.

Beyond prostate cancer, enzalutamide was explored experimentally in drug-resistant glioblastoma cells, where it enhanced honokiol-induced apoptotic injury through an intrinsic Bak-mitochondrion-caspase cascade mechanism. This suggests that enzalutamide can be used as a mechanistic probe in non-prostate cancer systems, particularly where androgen receptor-related signaling or drug-sensitization effects are being investigated. Additional work compared AR-TAD inhibitors with enzalutamide and found that several AR-TAD inhibitors had binding affinities comparable to or stronger than the ligand-binding-domain inhibitor enzalutamide, underscoring enzalutamide’s role as a benchmark compound in AR drug discovery.

Key Publications

• Jun Evolution of AR and Non-AR Alterations in ctDNA of Patients with Metastatic Prostate Cancer Treated in the Phase III Alliance A031201 Trial. (Clinical cancer research : an official journal of the American Association for Cancer Research, 2026, PMID 41587107): "Androgen receptor pathway inhibitors (ARPI), such as enzalutamide and abiraterone, are standard treatments for metastatic castration-resistant prostate cancer (mCRPC)."
• Jun Enzalutamide Enhanced Honokiol-induced Apoptotic Insults to Drug-resistant Glioblastoma Cells via an Intrinsic Bak-mitochondrion-caspase Cascade Mechanism. (Anticancer research, 2026, PMID 42203314): "This study was aimed to further evaluate the effects of enzalutamide, an inhibitor of AR, on honokiol-induced killing to drug-resistant glioblastoma cells and the possible mechanisms."
• May 131I-LNTH-1095 Radioligand Therapy plus Enzalutamide versus Enzalutamide Alone in Men with PSMA-Avid Metastatic Castration-Resistant Prostate Cancer: A Phase II Study. (Clinical cancer research : an official journal of the American Association for Cancer Research, 2026, PMID 41779000): "...in combination with enzalutamide in subjects with metastatic castration-resistant prostate cancer..."
• May Diminished expression of decorin drives enzalutamide resistance in CRPC by suppressing ACSL4-dependent lipid remodeling and ferroptosis. (International immunopharmacology, 2026, PMID 41861540): "Enzalutamide is a potent androgen receptor (AR) inhibitor widely used for the treatment of castration-resistant prostate cancer (CRPC)."
• May IGFBP3-SphK1/S1P Signaling Axis Drives Enzalutamide Resistance in Advanced Prostate Cancer. (Molecular cancer therapeutics, 2026, PMID 41347288): "Enzalutamide resistance remains a significant challenge in the treatment of advanced prostate cancer."
• May MECOM Function Is Critical for AR-Driven Treatment-Resistant Prostate Cancer. (Cancer research, 2026, PMID 41529070): "MECOM was exclusively overexpressed in both CRPC and enzalutamide-resistant CRPC and interacted with AR in the nucleus."
• May Radiographic Progression With and Without Prostate-Specific Antigen Rise in Patients With Advanced Prostate Cancer Treated With Enzalutamide. (Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2026, PMID 41894648): "In patients who received enzalutamide, we characterized the development of radiographic progression (rPD) without prostate-specific antigen (PSA) rise or progression in metastatic hormone-sensitive prostate cancer (mHSPC) and nonmetastatic castration-resistant prostate cancer (nmCRPC)."
• May Single-cell imaging analysis, therapeutic modeling and a Phase Ib trial validate BCL-2 as a target across heterogeneous castration-resistant prostate cancer. (Signal transduction and targeted therapy, 2026, PMID 42067541): "A Phase Ib clinical trial (NCT03751436) combining enzalutamide and BCL-2 inhibitor venetoclax demonstrated reduced circulating tumor cells in responding patients."
• Apr Drugging the intrinsically disordered transactivation domain of androgen receptor. (Signal transduction and targeted therapy, 2026, PMID 42045150): "Biophysically, several ARTADIs displayed exceptionally strong binding affinities that were better than, or were comparable to the LBD-inhibitor enzalutamide, with dissociation constants in the picomolar to low-nanomolar range as determined by surface plasmon resonance and microscale thermophoresis."
• Apr Neoadjuvant/adjuvant relugolix and enzalutamide for the treatment of high-risk locally advanced prostate cancer: study protocol of the RENAPCA phase Ib trial. (BMJ open, 2026, PMID 42031503): "Relugolix and enzalutamide have demonstrated strong efficacy independently in the setting of advanced disease, but their combined use in neoadjuvant/adjuvant therapy has not been studied."