P1, N=40, Active, not recruiting, Arvinas Androgen Receptor, Inc. | Trial primary completion date: Apr 2024 --> Jul 2024

P1, N=28, Terminated, Accutar Biotechnology Inc | Trial completion date: Nov 2024 --> Mar 2024 | Active, not recruiting --> Terminated; Subject benefit-risk ratio changes, sponsor decides to voluntarily terminate study

Compound D-4-6 exhibited significant AR protein degradation activity, with a degradation rate of 57 % at 5 μM and nearly 90 % at 20 μM in 24 h, and inhibited the proliferation of LNCaP cells significantly with an IC50 value of 4.77 ± 0.26 μM in a time-concentration-dependent manner. In conclusion, the present study lays the foundation for the development of a completely new class of therapeutic agents for the treatment of mCRPC, and further design and synthesis of AR-targeting degraders are currently in progress for better degradation rate.

P1, N=62, Recruiting, Hinova Pharmaceuticals Inc. | Not yet recruiting --> Recruiting

P1, N=22, Completed, Hinova Pharmaceuticals Aus Pty Ltd | Active, not recruiting --> Completed

P1, N=8, Terminated, Accutar Biotechnology Inc | Trial completion date: Jan 2026 --> Oct 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Jan 2025 --> Oct 2023; Subject benefit-risk ratio changes, sponsor decides to voluntarily terminate study

HP518, a novel AR PROTAC degrader, demonstrates in this Phase 1a dose-escalation study, an acceptable safety/tolerability profile and a signal of efficacy in an unselected mCRPC patient population. The presence of AR LBD mutations may predict benefit from HP518, and merits further investigation in pts with mCRPC. Clinical trial information: NCT05252364.

Pts with mCRPC who progressed on androgen deprivation therapy, ≥ 1 second generation hormonal therapy (eg, enzalutamide [enza], abiraterone [abi], darolutamide, and apalutamide) and taxane chemotherapy (chemo) (unless refused or not indicated) were enrolled to evaluate the safety, tolerability, PK/PD, and preliminary efficacy of CC-94676... As of Aug 21, 2023, 95 pts received CC-94676 (median age 71 yrs) with a median of 5 (range 2–12) prior therapies, including enza (80%), abi (72%), both enza & abi (56%), and chemo (56%) (docetaxel 55%; cabazitaxel 20%)... CC-94676 is well tolerated with a manageable safety profile. CC-94676 shows promising and prolonged clinical activity in heavily pretreated mCRPC pts who progressed on abi, enza, and chemo with activity seen in pts with tumors expressing WT and mutant ARs. Selection of the recommended phase 2 dose is ongoing.

Background: Current therapeutic strategies for metastatic castration-resistant prostate cancer (mCRPC) include treatment with next-generation androgen receptor signaling inhibitors (ARSIs), such as enzalutamide, darolutamide, and apalutamide, which all target the ligand-binding domain (LBD) of the AR, and abiraterone, an androgen biosynthesis inhibitor. The study was opened for enrollment September 2023. Clinical trial information: NCT05917470.

P1/2, N=220, Recruiting, Arvinas Androgen Receptor, Inc. | N=150 --> 220 | Trial completion date: Jun 2025 --> Jun 2026 | Trial primary completion date: Dec 2024 --> Dec 2025

P1, N=62, Not yet recruiting, Hinova Pharmaceuticals Inc.

P1, N=40, Active, not recruiting, Arvinas Androgen Receptor, Inc. | Phase classification: P1b --> P1 | Trial completion date: Jun 2024 --> Dec 2025 | Trial primary completion date: Nov 2023 --> Apr 2024

P1/2, N=250, Active, not recruiting, Arvinas Androgen Receptor, Inc. | Recruiting --> Active, not recruiting

P1, N=250, Recruiting, Celgene | N=170 --> 250 | Trial completion date: Feb 2025 --> Dec 2026 | Trial primary completion date: Aug 2023 --> Jun 2025

Inhibitory efficacy on N-myristoyltransferase activity by d-NMAPPD is stereospecific. (1R,2R)-LCL204 reduced global N-myristoylation and androgen receptor protein levels at low micromolar concentrations in prostate cancer cells. pharmacological inhibition of NMT1 enhances ubiquitin-mediated proteasome degradation of AR. This study illustrates a novel function of N-myristoyltransferase and provides a potential strategy for treatment of CRPC.

P1, N=8, Active, not recruiting, Accutar Biotechnology Inc | Recruiting --> Active, not recruiting | N=150 --> 8

P1, N=22, Active, not recruiting, Hinova Pharmaceuticals Aus Pty Ltd | Trial completion date: Mar 2025 --> Mar 2024

P1, N=36, Active, not recruiting, Accutar Biotechnology Inc | Recruiting --> Active, not recruiting | Trial completion date: Mar 2024 --> Nov 2024 | Trial primary completion date: Mar 2023 --> Apr 2024

No abstract available

In vivo, 23-h effectively inhibited the growth of hormone-sensitive organs in the Hershberger assay and exhibited robust antitumor efficacy both in enzalutamide-sensitive (LNCaP/AR) and enzalutamide-resistant (C4-2b-ENZ) xenograft models. Thus, 23-h was chosen as a preclinical candidate for the treatment of enzalutamide-resistant prostate cancer.

There were no grade ≥4 treatment-related adverse events (TRAEs) with 420 mg bavdeg (n=158 across phase 1/2); any grade TRAEs reported in ≥20% of pts were nausea (54%; 1% grade 3), fatigue (35%; 1% grade 3), vomiting (31%; 1% grade 3), diarrhea (25%; 2% grade 3) and decreased appetite (23%; 0 grade 3). Conclusions Bavdeg had encouraging efficacy in post-NHA pts with mCRPC and AR 878/875 or any AR missense LBD mutation (excluding AR L702H alone) and was tolerable; these pt populations will be analyzed in a phase 3 study of bavdeg.

P1/2, N=59, Not yet recruiting, Oncternal Therapeutics, Inc

P1/2, N=250, Recruiting, Arvinas Androgen Receptor, Inc. | Trial completion date: Oct 2023 --> Nov 2024 | Trial primary completion date: Feb 2023 --> Mar 2024

Since the progression of ARV-110 (PROTAC for PC) into clinical phases, the focus of research has quickly shifted to protein degraders targeting prostate cancer...We also delve into the underlying pathophysiology of the disease and explain the structural design and linkerology strategies for PROTAC molecules. Additionally, we touch on the various targets for PROTAC in prostate cancer, including the androgen receptor (AR) and other critical oncoproteins, and discuss the future prospects and challenges in this field.

ARV-766 significantly and dose-dependently inhibits tumor growth in murine LNCaP and VCaP xenograft models, including an enzalutamide-insensitive non-castrated VCaP model. These preclinical data supported the clinical development of ARV-766 for the treatment of men with metastatic CRPC. Selected pre-clinical data along with the chemical structure of ARV-766 will be presented.

Then, we built and characterized ternary complexes to validate previous results. Finally, we implemented machine learning classification models and showed that AR degradation for VHL-based but not CRBN-based PROTACs can be predicted from simple permeability-related 2D molecular descriptors.

Different types of AR degraders have been developed, including the proteolysis-targeting chimeras (PROTACs), selective AR degraders (SARDs), and novel AR degraders, with several AR PROTACs currently in clinical trials. The present mini-review discusses the regulation of AR degradation by the UPS, the potential role of a novel nuclear degradation signal in AR, and different types of AR degraders.

Patients enrolled in the cohort expansion must have received 1–3 prior NHAs (eg, abiraterone or enzalutamide) and ≤2 prior chemotherapy regimens. Enrollment in the phase 2 expansion study is ongoing. Clinical trial information: NCT05067140.

In conclusion, some indoles that activate AhR possess AR-inhibiting activity, which seems to be related to the downregulation of AR expression rather than to AR degradation alone. Moreover, there does not seem to be a clear relationship that would connect AhR activation with AR activity suppression in 22Rv1 cells.

Especially, the first PROTAC to enter the clinic, ARV-110, has shown good clinical effects in patients with mCRPC. This fully demonstrates the high clinical value of PROTAC strategy in treatment of human diseases. Here, we summarized the recent advances in the development of these potential clinical-stage PROTAC AR degraders.

Herein, we provide a comprehensive summary of small-molecule AR degraders with diverse mechanisms of action including proteolysis-targeting chimeras (PROTACs), selective AR degraders (SARDs), hydrophobic tags (HyT), and other AR degraders with distinct mechanisms. Accordingly, their structure-activity relationships, biomedical applications, and therapeutic values are also dissected to provide insights into the future development of promising AR degradation-based therapeutics for CRPC.

The role of the androgen receptor (AR) in HCC has been well documented; however, AR-targeted therapies have failed to demonstrate efficacy in HCC. Building upon understandings of AR in prostate cancer (PCa), this review examines the role of AR in HCC, non-androgen-mediated mechanisms of induced AR expression, the existence of AR splice variants (AR-SV) in HCC and concludes by surveying current AR-targeted therapeutic approaches in PCa that show potential for efficacy in HCC in light of AR-SV expression.

Here we review the existing treatment options in men with advanced prostate cancer, the market opportunity within this field, goals of current research, and the novel agents under investigation, including androgen receptor degraders, testosterone synthesis pathway inhibitors, DNA-binding domain and N-terminal domain antagonists, and the combination of hormonal and non-hormonal agents. Combination therapy regimens and novel agents targeting alternative binding domains of the androgen receptor are of great interest, as they may overcome resistance mechanisms and hold promise as the future of advanced prostate cancer treatment.

Herein, systemic structural modifications on the C-3, C-6, and C-17 positions of galeterone led to the discovery of 67-b with the dual functions of AR antagonism and degradation. In vivo, 67-b effectively inhibited the growth of hormone-sensitive organs in the Hershberger assay and exhibited tumor regression in the enzalutamide-resistant (c4-2b-ENZ) xenograft model. These results confirmed 67-b to be a promising AR degrader and antagonist for the treatment of mCRPC patients.

More recently, heterobifunctional degrader molecules of AR have been developed, and four such compounds are now in clinical development for the treatment of human prostate cancer. This review attempts to summarize the different types of compounds designed to target AR and the current frontiers of research on this important therapeutic target.

"Today Foundation Medicine, Inc...announced a collaboration with Arvinas, Inc., to develop FoundationOne®Liquid CDx as a companion diagnostic for use with Arvinas’ bavdegalutamide (ARV-110), an investigational novel PROTAC® protein degrader targeting the androgen receptor (AR). Arvinas’ bavdegalutamide is being developed for the potential treatment of men with metastatic castration resistant prostate cancer (mCRPC) who have progressed on existing therapies."

MDM2-p53 inhibitor (XR-2) possesses potently prostate cancer progresses inhibition activity both in vitro and in vivo. XR-2 shows a synergistic effect with enzalutamide and overcomes enzalutamide resistance.

The most clinically advanced proteolysis-targeting chimera, bavdegalutamide, seems to work best against two molecularly defined subtypes of advanced prostate cancer. According to phase I/II trial data presented at the 2022 American Society of Clinical Oncology Genitourinary Cancers Symposium, the androgen receptor degrader most commonly shows antitumor activity among patients with T878X or H875Y mutations.

Prior treatment with enzalutamide, apalutamide, darolutamide, or experimental AR-directed therapies is not permitted. Bavdegalutamide, abiraterone, and a corticosteroid will be administered daily in 28-day cycles. Primary objectives are to evaluate the safety and tolerability of bavdegalutamide plus abiraterone and determine the recommended phase 2 dose and schedule of this combination (based on the incidence of first-cycle dose-limiting toxicities and the frequency and severity of adverse events and laboratory abnormalities).