enzalutamide

Overview

Enzalutamide is a second-generation nonsteroidal Androgen receptor (AR) (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 (AR) 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.

Recent Publications Summary

Recent publications on enzalutamide have focused largely on prostate cancer, spanning real-world safety surveillance, biomarker and resistance studies, and combination or sequencing strategies. A FAERS disproportionality analysis compared post-marketing adverse event reporting for enzalutamide, olaparib, and lutetium Lu-177 vipivotide tetraxetan in prostate cancer, with time-dependent and age-stratified signal detection and a descriptive review of sparse concomitant-use reports involving all three agents 42446704Jul. Another study examined radiographic progression occurring without a prostate-specific antigen rise in patients with advanced prostate cancer treated with enzalutamide, specifically in metastatic hormone-sensitive prostate cancer and nonmetastatic castration-resistant prostate cancer 41894648Mar.

Several reports addressed enzalutamide in combination regimens. The phase II ARROW study evaluated 131I-LNTH-1095 radioligand therapy plus enzalutamide versus enzalutamide alone in men with PSMA-avid metastatic castration-resistant prostate cancer after progression on abiraterone 41779000Mar. A phase Ib RENAPCA trial protocol described neoadjuvant/adjuvant relugolix plus enzalutamide for high-risk locally advanced prostate cancer, aiming to assess safety and efficacy alongside definitive local treatment 42031503Apr. In high-risk biochemical recurrence, EMBARK secondary end points further examined enzalutamide monotherapy versus leuprolide alone, extending the phase 3 trial’s earlier efficacy and safety findings 41349040Dec.

Mechanistic and resistance-focused studies also featured enzalutamide as a key comparator or tool compound. Longitudinal ctDNA analysis from the phase III Alliance A031201 trial investigated AR and non-AR genomic alterations associated with resistance to androgen receptor pathway inhibitors, including enzalutamide and abiraterone, in metastatic prostate cancer 41587107Jan. A separate study on drugging the intrinsically disordered transactivation domain of the androgen receptor discussed the broader challenge of resistance to ligand-binding-domain targeting and used prostate cancer cell and xenograft models to evaluate AR-TAD inhibitors in relation to AR and AR-V7 signaling 42045150Apr. Outside prostate cancer, enzalutamide was tested in glioblastoma models, where it enhanced honokiol-induced apoptosis in drug-resistant glioblastoma cells through an intrinsic Bak-mitochondrion-caspase cascade mechanism 42203314May.

What Changes, What Holds

1. Post-marketing and progression-pattern data refine enzalutamide’s risk and monitoring profile
METHOD Real-world pharmacovigilance and imaging-pattern analyses do not alter enzalutamide’s established role as an AR inhibitor, but they do sharpen how it should be followed in practice. The safety signal work adds post-approval surveillance context for use alongside other advanced prostate cancer agents, while the radiographic-progression finding highlights that PSA alone may miss clinically relevant progression in some treated patients 42446704Jul41894648Mar.

2. Combination and sequencing studies extend enzalutamide into new treatment strategies without displacing its core mechanism
NEW DIRECTION These reports do not challenge the Overview’s account of enzalutamide as an AR-pathway blocker; instead, they broaden its therapeutic context into radioligand combinations, perioperative intensification, and biochemical-recurrence sequencing. The main implication is that enzalutamide is increasingly being positioned as a backbone or comparator in multi-modality regimens, but the optimal place of these strategies remains unsettled and will depend on whether added benefit outweighs cumulative toxicity and complexity 41779000Mar42031503Apr.

3. Resistance biology now points to genomic escape routes beyond the androgen receptor ligand-binding domain
REINFORCES Longitudinal ctDNA work strengthens the baseline view that enzalutamide is a central probe for castration-resistant disease biology by showing how resistance can be tracked through evolving AR and non-AR alterations. Rather than revising the drug’s mechanism, this deepens the picture of why ligand-binding-domain targeting eventually fails and supports the need for biomarkers that can distinguish AR-dependent from AR-independent escape 41587107Jan.

4. Targeting the androgen receptor transactivation domain remains a plausible way around enzalutamide-class resistance
REINFORCES Work on intrinsically disordered AR transactivation-domain inhibition does not replace enzalutamide’s established mechanism; it reinforces the rationale for moving beyond ligand-binding-domain blockade when AR-V7 or related resistance states emerge. The important consequence is conceptual: enzalutamide remains the benchmark comparator, but the new data keep AR-TAD inhibition in the category of a credible next-step strategy rather than a proven substitute 42045150Apr.

5. Enzalutamide may have activity outside prostate cancer, but that role is still exploratory
NEW DIRECTION The glioblastoma findings sit outside the Overview’s prostate-cancer-centered account and therefore add a new potential use rather than revising the established one. They suggest enzalutamide can participate in pro-apoptotic combinations in a non-AR tumor context, but the evidence is preclinical and does not yet establish a generalizable oncology role beyond prostate cancer 42203314May.

Overview update candidates: PSA-discordant radiographic progression during enzalutamide therapy; emerging real-world safety surveillance; exploratory non-prostate-cancer activity remains too preliminary for the Overview.