bavdegalutamide (ARV-110) / Arvinas - LARVOL DELTA

Phase I/II study of bavdegalutamide, a PROTAC androgen receptor (AR) degrader in metastatic castration-resistant prostate cancer (mCRPC): Radiographic progression-free survival (rPFS) in patients (pts) with AR ligand-binding domain (LBD) mutations (ESMO 2023) - P1/2 | "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."

Clinical • Metastases • P1/2 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

Long-Term Stabilization of Non-Bovine Milk Exosomes Using Lyophilization: Toward Oral Delivery of PROTAC Therapeutics. (PubMed, J Drug Deliv Sci Technol) - "We developed and optimized a lyophilization protocol to stabilize camel and donkey milk-derived exosomes for oral delivery of ARV-110, a proteolysis-targeting chimera (PROTAC)...Lyophilized exosomes retained over 90% of protein content after 8 weeks at -80°C, whereas non-lyophilized controls retained <25%. These findings demonstrate that lyophilized milk exosomes are a scalable, biocompatible platform for oral delivery of poorly bioavailable therapeutics like PROTACs, addressing major formulation and stability challenges and supporting their translational potential in drug delivery."

Journal • Targeted Protein Degradation • CD63 • CD81 • TSG101

Phase 1b trial of Bavdegalutamide (ARV-110) in combination with Abiraterone for metastatic prostate cancer. (PubMed, Clin Cancer Res) - "Bavdegalutamide combined with abiraterone demonstrated a manageable safety profile with no major drug-drug interaction and evidence of clinical activity in mPC."

Journal • P1 data • Fatigue • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation

Can PROTACs truly become oral drugs? (PubMed, Drug Discov Today) - "Although a growing number of PROTACs are administered orally in clinical studies, and several have demonstrated measurable systemic exposure and pharmacodynamic activity (such as ARV-110, ARV-471, and BMS-986365), the ability to reliably design PROTACs with predictable oral bioavailability remains limited. We argue that the field will benefit greatly from adopting an 'oral-first' conformation-centric approach, discovering new E3 ligases and ligands, earlier predictive modeling, and strategic formulation technologies. Progressing alternative modalities in parallel might further expand opportunities for developing orally viable protein-elimination therapies."

Journal • Review • Targeted Protein Degradation • CRBN

AR PROTAC ARV-110 improves motor dysfunction in a mouse model of spinal and bulbar muscular atrophy (JSNE 2026) - No abstract available

Preclinical • Muscular Atrophy • Targeted Protein Degradation

Bellerophon: An Automated Tool for PROTAC Decomposition. (PubMed, ACS Med Chem Lett) - "By enabling automated and standardized decomposition of degraders, the tool facilitates drug design at different levels: Bellerophon demonstrated versatility for moiety replacement (ARV-110), large-scale annotation (PROTAC-DB) and linker analysis (IRAK4 data set). The tool is freely available through a user-friendly web interface, with open-source code to encourage transparency and collaborative development in chemical biology and medicinal chemistry."

Journal • Targeted Protein Degradation • IRAK4

The In Vivo Effect of Amorphous Drug Nanoprecipitates on the Intestinal Absorption of the PROTACs ARV-110 (Bavdeglutamide) and ARV-471 (Vepdegestrant). (PubMed, Mol Pharm) - "For the more soluble ARV-471, the colloid effect persisted at doses up to 5.0 mg/kg but at a reduced rate due to the formation of larger, less mobile particles. Overall, this work provided mechanistic insight into PROTAC absorption and suggested that formulations capable of generating stable amorphous drug nanoprecipitates represent a promising strategy to enhance the oral bioavailability of low-solubility PROTACs."

Journal • Preclinical • Targeted Protein Degradation

An orally bioavailable AR-NTD degrader that bypasses LBD-dependent resistance and prevents AR-V7-mediated feedback in advanced prostate cancer (AACR 2026) - "In enzalutamide-resistant C4-2B/MDVR cells, ITRI-148 exhibited superior antiproliferative activity compared with enzalutamide and the LBD-targeted degrader ARV-110. Toxicokinetic studies in rats showed favorable systemic exposure without significant body weight loss or hematologic toxicity at therapeutic doses. Collectively, these findings establish ITRI-148 as a pan-AR degrader that bypasses LBD-dependent resistance mechanisms and prevents AR-V7-mediated feedback, supporting its potential as a next-generation therapy for advanced CRPC."

Late-breaking abstract • Metastases • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • CRBN

First-in-class dual AR/AR-V7 molecular glue degraders targeting the undruggable N-terminal domain to overcome therapeutic resistance in prostate cancer (AACR 2026) - "Clinically, AR-V7 expression is strongly associated with resistance to all AR pathway inhibitors (ARPIs), including enzalutamide and abiraterone...In vivo, pharmacokinetic (PK)-optimized compounds significantly suppressed tumor growth in the enzalutamide-resistant 22Rv1 xenograft model, reversed resistance, and outperformed ARV-110, the only full-length AR-PROTAC degrader in clinical trials, by >10-fold in efficacy, with no effect on mouse body weight—establishing both robust antitumor activity and excellent tolerability...By enabling dual degradation of AR (the initiating oncogenic driver in PC) and AR-V7 (the lethal, treatment-resistant variant), our drug candidate has the potential to transform the treatment landscape—benefiting patients with both hormone-sensitive and advanced castration-resistant disease, while delaying or preventing AR-V7-mediated progression. Ultimately, this work charts a new course for prostate cancer therapy by providing a first-in-class..."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • DDB1

Developing first-in-class AR-V7/AR-fl molecular glue degrader to revolutionize prostate cancer therapeutics (AACR 2025) - "Mechanistically, our lead compounds promoted Cullin-RING E3 ligase-mediated proteasomal degradation of AR-V7 and AR-fl within 4 hours, which was blocked by the proteasome inhibitor, bortezomib...Importantly, our lead compounds effectively reversed SoC treatment-resistance in preclinical models and demonstrated higher potency than enzalutamide or ARV-110 (AR-fl-PROTAC)...Collectively, these data support a first-in-class molecular glue degrader mechanism, enabling rapid degradation of both AR-fl and AR-V7 through targeting the AR NTD. In summary, our compounds offer a dual-targeting approach in a single treatment and have the potential to dramatically improve survival for patients with mCRPC and prevent the emergence of AR-V7 expression in patients with earlier-stage disease."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

Mechanism and therapeutic significance of ARV-110 combined with a PDGFR inhibitor for the induction of apoptosis in castration-resistant prostate cancer cells through the ROS/JNK pathway. (PubMed, Cell Death Dis) - "The combination of ARV-110 and ponatinib exerted a significant inhibitory and synergistic effect on CRPC cells. Additionally, the substantial accumulation of reactive oxygen species induced by the combination strategy was related to the joint downregulation of catalase by the two drugs through different mechanisms. In conclusion, this study described a new strategy for the treatment of CRPC and clarified the molecular mechanisms of the combination strategy, providing a new theoretical basis for the precision treatment of CRPC."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CAT • PDGFA

High-resolution functional mapping of androgen receptor variants. (PubMed, Nat Biomed Eng) - "This mapping identified 755 new non-functional AR variants and revealed 225 and 40 new variants resistant to enzalutamide and bavdegalutamide, an AR degrader, respectively. Our findings also enabled prognosis prediction for patients with prostate cancer based on AR mutation profiles. The broader implications of the study include improved androgen insensitivity syndrome diagnosis, better prostate cancer prognosis prediction and precision treatments for patients with prostate cancer."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

Discovery of ETS-007, a first-in-class degrader targeting N-terminal domain of androgen receptor derived from AR liquid-liquid phase separation inhibitor (AACR 2024) - "Compared with enzalutamide and ARV-110, ETS-007 could block transcriptional activities of AR-V7, and AR mutants in luciferase report assay. Oral administration of ETS-007 in an enzalutamide-resistant 22RV1 xenograft model led to intratumoral AR-V7 degradation and concomitant decrease in PSA protein levels, resulting in a remarkable tumor regression. Taken together, our findings provide preclinical evidence that ETS-007 as a potent AR-NTD degrader derived from our LLPS platform can effectively block the transcriptional activities of both AR and AR-V7 for the treatment of metastatic CRPC."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

PBPK Modelling of PROTACs: Learnings from ARV-110 as a Case Example. (PubMed, AAPS J) - "This model effectively captured plasma drug concentration-time profiles reported for preclinical and clinical studies, including studies involving impact of food and drug-drug interactions with itraconazole and esomeprazole. Following administration of a single dose (280 mg) of ARV-110, the observed vs. predicted AUC0-inf for high fat, medium fat and low fat studies were 13563.0 vs. 7646.0 ng.h/ml, 4358.0 vs. 4618.3 ng.h/ml and 1919.0 vs. 1403.3 ng.h/ml. This work provides a translational PBPK framework for predicting human oral PK of PROTACs and emphasizes challenges in generating robust preclinical data to enhance prediction accuracy."

Journal • Oncology • Targeted Protein Degradation

Androgen receptor-dependent DRAM1 activation drives autophagic resistance to BRAF inhibitors in BRAFV600-mutant melanoma. (PubMed, Cell Death Dis) - "Functional studies reveal that AR-driven autophagy confers resistance to BRAFi by enhancing cellular survival under therapeutic stress. Our findings establish AR-regulated autophagy as a critical resistance mechanism and provide preclinical evidence for combining AR-targeting PROTAC degrader ARV110 with autophagy inhibitors to overcome BRAFi resistance."

Journal • Melanoma • Oncology • Solid Tumor • Targeted Protein Degradation • AR

Preclinical translational physiologically based pharmacokinetic modeling for predicting human pharmacokinetics of proteolysis targeting chimeras: Case studies of vepdegestrant (ARV-471) and bavdegalutamide (ARV-110). (PubMed, Drug Metab Dispos) - "Incorporating mechanistic absorption modeling and permeability data from modified in vitro assays (Genentech Madin-Darby canine kidney cells with 4% bovine serum albumin) improved oral absorption predictions, whereas the integration of multispecies preclinical PK data enhanced the translational accuracy of human PK predictions. Together, these findings establish a translational physiologically based PK framework for estimating oral exposure in first-in-human studies and supporting model-informed development of proteolysis targeting chimeras drug candidates."

First-in-human • Journal • PK/PD data • Preclinical • Targeted Protein Degradation

Nanoliposomal Co-Delivery of AR-PROTAC and NFKBIZ siRNA for Synergistic Therapy of Androgenetic Alopecia. (PubMed, ACS Appl Bio Mater) - "In this study, we developed nanoliposomes (NLPs) formulation by self-assembling AR-PROTAC (ARV110) and NFKBIZ siRNA (siNFKBIZ) into nanoparticles, followed by surface modification with liposomes...Additionally, NLPs downregulate AR protein expression to modulate hair growth-associated signaling pathways, achieving a multimodal synergistic therapeutic effect for AGA. Our design offers an effective multi-target strategy for AGA, resulting in enhanced therapeutic effects for hair loss treatment."

Journal • Alopecia • Immunology • Inflammation • Targeted Protein Degradation • AR

Next-Generation Proteolysis-Targeting Chimeras in Precision Oncology: Multifunctional Designs, Emerging Modalities, and Translational Prospects in Targeted Protein Degradation. (PubMed, Drug Dev Res) - "Furthermore, ARV-110 and ARV-471, as two representative PROTACs, have entered clinical trials, suggesting their potentially broader application. Accordingly, this review provides a critical overview of the design rationales, molecular mechanisms of action, therapeutic utilities, and synthetic issues associated with these innovative modalities, focusing on on their translational implication and pharmacokinetic limitations, as well as potential future clinical applications."

Journal • Review • Oncology • Targeted Protein Degradation

Molecular Glue Degraders of AR/AR-V7: A Paradigm Shift in the Treatment of Advanced Prostate Cancer (PCF 2025) - "Clinically, AR-V7 is strongly associated with resistance to enzalutamide and abiraterone and is detected in >75% of advanced mCRPC cases, yet no inhibitors exist—underscoring a profound unmet need...In vivo, PK-optimized leads suppressed tumor growth in enzalutamide-resistant xenografts, outperformed ARV-110, the only AR-PROTAC degrader in clinical trials, by >10-fold, and showed excellent tolerability...Funding Acknowledgement: This work was supported by grants from the National Cancer Institute (NCI) Grant NIH T32 CA062948 (2020-2022) (C C Au), NIH-NCI Dual Fast Track phase I STTR/Phase II SBIR 1R42CA290913-01 (2024- 2027) (C C Au), First place of 2020 eBiomedical Business Plan Challenge (C C Au and P Giannakakou), The Daedalus Fund for Innovation award (P Giannakakou), The SPORE DRP award (P Giannakakou), DOD Grant W81XWH-19-1-0666 (P Giannakakou). I have the following relevant financial relationships to disclose: Co-founder of ARMA BIO, Corp"

Metastases • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • DDB1

Proteolysis-Targeting Chimera (PROTAC): Current Applications and Future Directions. (PubMed, MedComm (2020)) - "We evaluate clinical progression of breakthrough candidates such as ARV-110 for prostate cancer, ARV-471 for breast cancer, and BTK degraders, while discussing critical challenges including the "hook effect" and oral bioavailability limitations. This review provides essential foundations for rational target selection, molecular optimization, and clinical translation strategies. By integrating mechanistic insights with clinical realities, this analysis offers perspectives on PROTAC technology advancement and identifies opportunities for transforming treatment of complex diseases resistant to conventional therapies."

Journal • Review • Breast Cancer • Genito-urinary Cancer • Hormone Receptor Breast Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • KRAS • STAT3

Covalent destabilizing degrader of AR and AR-V7 in androgen-independent prostate cancer cells (ACS-Fall 2025) - "Consistent with targeting both AR and AR-V7, we find that our molecule completely inhibits total AR transcriptional activity in androgen-independent prostate cancer cells expressing both AR and AR-V7 compared to AR antagonists or degraders that only target the ligand binding domain of full-length AR, such as enzalutamide and ARV-110. Taken together, our results highlight the utility of covalent ligand discovery approaches in directly targeting, destabilizing, inhibiting, and degrading classically undruggable transcription factor targets."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

In-cell proximity target validation methods for heterobifunctional molecules with CRBN- or VHL-binder using AirID. (PubMed, Commun Biol) - "Currently, cereblon (CRBN)- and von Hippel-Lindau (VHL)-binders with thalidomide- and VH032-backbones are widely used as E3 ligase binders. Analysis using ThBD-AirID revealed a nuclear interaction between androgen receptor and ARV-110. AirID-fused ThBD and VHL could be useful for validating the heterobifunctional molecular interactome in cells."

Journal • Targeted Protein Degradation • Von Hippel-Lindau Syndrome • AR • CRBN

Trial of ARV-110 and Abiraterone in Patients With Metastatic Castration Resistant Prostate Cancer (mCRPC) (clinicaltrials.gov) - P1 | N=45 | Completed | Sponsor: Arvinas Androgen Receptor, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Dec 2025 ➔ Apr 2025

Trial completion • Trial completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

Synthesis of Two Versions of Carbon-14-Labeled ARV-110: An Androgen Receptor PROTAC Degrader for Prostate Cancer. (PubMed, J Labelled Comp Radiopharm) - "To support preclinical safety evaluations as well as studies of drug metabolism and pharmacokinetics, two versions of carbon-14-labeled ARV-110 were synthesized: N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-[1,3-14C2]dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide (14C-ARV-110-a) and N-((1R,4R)-4-(3-chloro-4-[cyano-14C]cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide (14C-ARV-110-b). The synthesis of 14C-ARV-110-a was initiated from 1,2-dibromo-4,5-difluorobenzene and zinc cyanide-14C (Zn(14CN)₂), while 14C-ARV-110-b was prepared from 2-chloro-4-fluoro[cyano-14C]benzonitrile."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • AR

Renal and Hepatic Effects of Androgen Receptor Downregulation by PROTAC ARV-110 in a Mouse Model of Polycystic Ovary Syndrome (ENDO 2025) - "DHT-VEH mice showed significant (p<0.05) increases in BW (1.14-fold), fat mass (2-fold), lean mass (1.09-fold), FG (1.29-fold), and impaired glucose tolerance (OGTT, AUC 1.47-fold) compared to CON-VEH. Both ARV-L and ARV-H treatments in DHT mice reduced BW, fat mass, FG, and OGTT without affecting lean mass. DHT-VEH-treated mice had increased kidney weight, UACR, and NGAL levels which were attenuated by ARV-110 in a dose-dependent manner."

Preclinical • Endocrine Disorders • Genetic Disorders • Genito-urinary Cancer • Hepatology • Liver Failure • Metabolic Disorders • Nephrology • Obesity • Oncology • Polycystic Ovary Syndrome • Prostate Cancer • Renal Disease • Solid Tumor • Targeted Protein Degradation • AR • KIM1