Androgen receptor (AR) signaling is the principal driver of prostate cancer, and drugs that target this pathway (e.g., abiraterone and enzalutamide) are standard treatments for metastatic hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer (mCRPC). These promising preclinical data supported clinical development of bavdegalutamide as a potential treatment for patients with prostate cancer. Bavdegalutamide was the first PROTAC protein degrader to enter human clinical trials, specifically in patients with mCRPC in a phase 1/2 study (NCT03888612).

P1, N=24, Recruiting, Celgene | Trial completion date: Sep 2024 --> Feb 2025 | Trial primary completion date: Sep 2024 --> Feb 2025

P2, N=180, Completed, Suzhou Kintor Pharmaceutical Inc,

P1, N=250, Active, not recruiting, Celgene | Recruiting --> Active, not recruiting

P1, N=24, Recruiting, Atridia Pty Ltd. | Not yet recruiting --> Recruiting

P1, N=24, Recruiting, Celgene | Not yet recruiting --> Recruiting

P1/2, N=21, Terminated, Oncternal Therapeutics, Inc | N=59 --> 21 | Trial completion date: Jan 2028 --> Sep 2024 | Recruiting --> Terminated | Trial primary completion date: Jan 2028 --> Sep 2024; Interim Phase 1 results of ONCT-534 did not show clinically meaningful improvements of disease, including prostate-specific antigen (PSA) levels, in the 20 patients treated in eight dosing cohorts with various doses and schedules of administration.

P1/2, N=100, Recruiting, Jiangsu HengRui Medicine Co., Ltd. | Not yet recruiting --> Recruiting

P1/2, N=100, Not yet recruiting, Jiangsu HengRui Medicine Co., Ltd.

P1, N=24, Not yet recruiting, Atridia Pty Ltd.

In androgen receptor suppression study, compounds 1f and 2g show similar androgen receptor suppression effect as compared to ASC-J9 on C4-2 cells, compound 3c displays significantly enhanced AR suppression effect as compared to ASC-J9, 1f and 2g. Compounds 1a, 1e, 1f, 1h, 2g, 3a and 3c prepared in this work have significant potential for castration-resistant prostate cancer therapy.

Compound 22 (AZ'3137) possessed an attractive profile showing degradation of AR and L702H mutant AR with good oral bioavailability across species. The compound also inhibited AR signaling in vitro and tumor growth in vivo in a mouse prostate cancer xenograft model.

Here, the study reports a novel cereblon-based AR degrader, UBX-390, and demonstrates its superior activity over established AR degraders, such as ARV-110 or ARCC-4, in prostate cancer cells under short- and long-term treatment conditions. UBX-390 suppresses chromatin binding and gene expression of AR and demonstrates substantial efficacy in the degradation of AR mutants in patients with treatment-resistant prostate cancer. UBX-390 is presented as an optimized AR degrader with remarkable potential for treating castration-resistant prostate cancer.

In vivo experiments further confirmed the anti-tumor activity, safety, and effect on androgen receptor level of TE5 in animal models of GBM. Our results suggest that TE5 may be a potential therapeutic drug to treat GBM.

P1, N=82, Recruiting, Celgene | Not yet recruiting --> Recruiting

P1, N=92, Completed, Suzhou Kintor Pharmaceutical Inc,

P1, N=24, Not yet recruiting, Celgene

These biphenyl derivatives exhibited potent antiproliferative activity against LNCaP and 22Rv1 cells. Our discoveries enrich the diversity of small molecule AR degraders and offer insights for the development of novel AR degraders for the treatment of enzalutamide-resistant prostate cancer.

P1, N=82, Not yet recruiting, Celgene

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