Xtandi (enzalutamide capsule)

This analysis suggests that the Decipher genomic classifier may be prognostic for disease progression in AS patients with low- to intermediate-risk prostate cancer. Higher Decipher and AR-A scores, as well as PAM50 luminal subtypes, may also serve as biomarkers for treatment response.

P1/2, N=40, Enrolling by invitation, Zenith Epigenetics | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P2, N=200, Recruiting, Zenith Epigenetics | Phase classification: P2b --> P2 | Trial completion date: Sep 2024 --> Jun 2025 | Trial primary completion date: Mar 2024 --> Dec 2024

The androgen receptor AR antagonists, such as enzalutamide and apalutamide, are efficient therapeutics for the treatment of prostate cancer (PCa). It potently inhibits cell growth with IC50 values of 4.87 ± 0.52 and 2.07 ± 0.34 μM in the LNCaP and 22RV1 cell lines, respectively, and exhibited effective tumor growth inhibition (TGI = 50.9 %) in the 22RV1 xenograft study. These data suggest that 20i has the potential for development as an AR/AR-V7 inhibitor with degradation ability to treat advanced prostate cancer.

P2, N=30, Active, not recruiting, Instituto do Cancer do Estado de São Paulo | Trial completion date: Jul 2023 --> Apr 2025 | Trial primary completion date: Mar 2023 --> Mar 2024

P=N/A, N=42, Active, not recruiting, Medical College of Wisconsin | N=60 --> 42

Here, we review the newly approved PARPi plus ARSI treatments within the context of the mCRPC treatment landscape, provide an overview of practical considerations for the combinations in clinical practice, highlight the importance of HRR testing, and discuss the benefits of treatment intensification for patients with mCRPC.

The data suggest that the cargo of exosomes is controlled by AR-agonist and -antagonists and distinct among the AR-antagonists. Further, exosomes promote growth that might influence the TME. This finding sheds light into the complex interplay between AR signaling and exosome-mediated communication between PCa cells.

Enzalutamide interactions with common vitamins and supplements are also briefly discussed. This review provides a resource for healthcare practitioners and patients that will help provide a basis for the understanding and management of enzalutamide drug-drug interactions to inform decision making, improve patient safety, and optimize drug efficacy.

P2, N=1500, Recruiting, Bristol-Myers Squibb | N=800 --> 1500 | Trial completion date: Aug 2025 --> Aug 2029 | Trial primary completion date: Aug 2025 --> Aug 2029

This study confirmed that the combination of histone deacetylase (HDAC) inhibitors and androgen receptor (AR) antagonists possessed greater therapeutic efficacy than monotherapy in LAR TNBC. This finding significantly bolsters the theoretical basis for the clinical translation of this combination therapy and provides an innovative strategy for the targeted treatment of LAR TNBC.

P2, N=90, Recruiting, University of Chicago | Not yet recruiting --> Recruiting

Here, we demonstrate that AR is highly expressed in DSRCT relative to other fusion-driven sarcomas and that the AR antagonists enzalutamide and flutamide reduce DSRCT growth. Further, we find that AR antagonists reduce DSRCT growth in cells depleted of AR, establishing an AR-independent mechanism of action. These findings suggest that AR dependence is not the reason for male predominance in DSRCT and that AR-targeted therapies may provide therapeutic benefit primarily through an AR-independent mechanism that requires further elucidation.

P=N/A, N=1800, Completed, Bayer | Active, not recruiting --> Completed

P2, N=79, Active, not recruiting, Alliance for Clinical Trials in Oncology | Recruiting --> Active, not recruiting

We also found that the EZH2/SFRP1/WNT5A axis may be involved in this role. These findings open new avenues for treating bone metastatic and Enz-resistant CRPC.

Activated AR/ORC1 axis contributed to enzalutamide resistance, and targeting ORC1 rendered PRAD cells more susceptible to enzalutamide. This study defines an AR-driven signature that AR activates ORC1 expressions to promote PRAD progression and enzalutamide resistance, which may provide novel targets for PRAD treatment.

AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients. The ABCB1 inhibitor, zosuquidar, reversed resistance to all three PROTAC degraders tested. Combined, these findings position mSWI/SNF degraders for clinical translation for patients with enhancer-driven cancers and define strategies to overcome resistance mechanisms that may arise.

P3, N=688, Completed, Astellas Pharma Europe Ltd. | Active, not recruiting --> Completed

P3, N=446, Active, not recruiting, European Organisation for Research and Treatment of Cancer - EORTC | Trial completion date: Dec 2025 --> Dec 2028

P1/2, N=337, Recruiting, Pfizer | Trial completion date: Oct 2027 --> May 2028 | Trial primary completion date: Aug 2026 --> Mar 2027

Our results demonstrate that ADT led to a significant upregulation in MCT1 levels. However, the combination of ENZ and SR13800 demonstrated a promising synergistic anticancer effect, highlighting a potential therapeutic significance for patients with PCa undergoing ADT.

PTEN LOF, identified with genomic testing, was associated with decreased survival and negative prognoses in patients with mCRPC.

NEPC is associated with cell transdifferentiation and the epithelial-mesenchymal transition (EMT) in cells undergoing androgen deprivation therapy (ADT) and enzalutamide (ENZ)...REST behaves like a tumor suppressor, decreasing the aggressiveness of 22rv1 cells, probably through the repression of EMT and the neuroendocrine phenotype. Furthermore, REST could represent a response marker to ENZ in PCa patients.

P2, N=292, Active, not recruiting, Bristol-Myers Squibb | Trial completion date: Feb 2025 --> Sep 2024

Specifically, 229E induced luciferase-reporter activity in the presence and absence of the synthetic androgen mibolerone, while OC43 inhibited induction. These findings highlight a complex interplay between viral infections and androgen-signaling, offering insights for disparities in viral outcomes and antiviral interventions.

In this study, we examined the chromatin landscape of AR-positive prostate cancer cells post-exposure to the AR inhibitor enzalutamide...These effects were mediated through the downregulation of the Wnt/β-catenin signalling pathway and subsequent reduction of nuclear β-catenin. Collectively, our findings provide compelling evidence that the depletion of SIX2 may represent a promising strategy for overcoming the cell plasticity mechanisms driving antiandrogen resistance in prostate cancer.

P1, N=610, Not yet recruiting, Hansoh BioMedical R&D Company

P=N/A, N=979, Active, not recruiting, Janssen Pharmaceutical K.K. | Trial completion date: Aug 2024 --> Oct 2025 | Trial primary completion date: Aug 2024 --> Oct 2025

Indeed, the combination treatment awoke cytotoxic activity and IFN-γ production of tumor-specific CD8+ T lymphocytes. These results promote the combination of enzalutamide and GSK-126 in CRPC, also offering new avenues for immunotherapy in prostate cancer.

P2, N=214, Active, not recruiting, Centre hospitalier de l'Université de Montréal (CHUM) | Recruiting --> Active, not recruiting

P4, N=52, Completed, Astellas Pharma Inc | Active, not recruiting --> Completed

Importantly, 27c demonstrated potent antitumor efficacy in an enzalutamide-resistant 22RV1 xenograft model. These results highlight the potential of 27c as a promising dual AR/AR-V7 degrader for overcoming drug resistance in advanced PCa expressing AR splice variants.

P3, N=405, Active, not recruiting, pharmaand GmbH | Trial completion date: Mar 2024 --> Dec 2024

P3, N=8000, Not yet recruiting, University College, London

P1/2, N=46, Completed, Sidney Kimmel Cancer Center at Thomas Jefferson University | Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Sep 2023

P2, N=35, Not yet recruiting, Pedro Barata, MD, MSc

Here, funnel metadynamics is employed to elucidate the inherent regulation mechanisms of three AR antagonists (hydroxyflutamide, enzalutamide, and darolutamide) on AR. Subsequently, docking-based virtual screening toward the dominant binding conformation of AR for darolutamide is conducted, and three novel AR antagonists with favorable binding affinity and strong capability to combat drug resistance are identified by in vitro bioassays. This work provides a novel rational strategy for the development of anti-resistant AR antagonists.

Based on the research of the AR pathway, new drugs for the treatment of CRPC have been developed in clinical practice, such as Abiraterone and enzalutamide. Based on correlation analysis and flow cytometry, we can speculate that AFF3 can impact the sensitivity of the CRPC cell lines to the ferroptosis inducer (RSL3) by regulating ACSL4. Therefore, our findings may provide new insights into the mechanisms of drug resistance in CRPC, and AFF3 may serve as a novel prognostic biomarker in prostate cancer.

P2, N=13, Completed, University of Michigan Rogel Cancer Center | Active, not recruiting --> Completed | Trial completion date: Mar 2024 --> Jul 2023

P2, N=25, Recruiting, Mayo Clinic | Not yet recruiting --> Recruiting

P3, N=1600, Not yet recruiting, European Organisation for Research and Treatment of Cancer - EORTC | Initiation date: Dec 2023 --> Jun 2024