bavdegalutamide (ARV-110) / Arvinas - LARVOL DELTA

CD36-mediated endocytosis of proteolysis-targeting chimeras. (PubMed, Cell) - "Here, using biotinylated chemical-probe-based target fishing and genetic knockdown/knockin approaches, we discovered that the membrane cluster of differentiation 36 (CD36) binds to and facilitates the uptake and efficacy of diverse PROTACs (e.g., SIM1-Me, MZ1, and clinical ARV-110) and large and/or polar small-molecule drugs (e.g., rapalink-1, rapamycin, navitoclax, birinapant, tubacin, and doxorubicin) via the CD36-mediated early endosome antigen 1 (EEA1)/Ras-related protein 5A (Rab5) endosomal cascade in vitro and/or in vivo. We then devised a novel chemical endocytic medicinal chemistry strategy to improve binding of PROTACs to CD36 using structural modifications via the prodrug approach, markedly enhancing PROTAC anti-tumor efficacy through spontaneously augmenting permeability and solubility."

Journal • Oncology • Targeted Protein Degradation • CD36 • RAB5A • SCARB1

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

A comprehensive mechanistic investigation of factors affecting intestinal absorption and bioavailability of two PROTACs in rats. (PubMed, Eur J Pharm Biopharm) - "In the rat, ARV-110 and ARV-471 were enzymatically degraded in the intestinal lumen and in plasma, and their intestinal permeability and systemic exposure seem to be reduced due to P-gp efflux."

Journal • Preclinical • Gastrointestinal Disorder • Targeted Protein Degradation

ARDENT: Trial of ARV-110 in Patients With Metastatic Castration Resistant Prostate Cancer (clinicaltrials.gov) - P1/2 | N=248 | Completed | Sponsor: Arvinas Inc. | Active, not recruiting ➔ Completed | Trial primary completion date: Jan 2025 ➔ Apr 2024

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

Conquering PROTAC molecular design and drugability. (PubMed, Bioanalysis) - "Clinical successes, including ARV-110 for castration-resistant prostate cancer and ARV-471 for breast cancer, exemplify their ability to overcome resistance and provide durable effects. By addressing challenges in pharmacokinetics, safety, and scalability, PROTACs are poised to revolutionize precision medicine. This article presents a forward-looking perspective on conquering the molecular design and drugability of PROTACs, paving the path for transformative therapies."

Journal • Breast Cancer • Castration-Resistant Prostate Cancer • CNS Disorders • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation

Microwave-assisted synthesis of pomalidomide building blocks for rapid PROTAC and molecular glue development. (PubMed, Chem Commun (Camb)) - "Unlike conventional oil bath heating and overnight reactions, MAS streamlines degrader development. The method's utility was demonstrated by synthesizing ARV-110, highlighting MAS as a powerful tool for accelerating pomalidomide PROTAC and molecular glue discovery programs."

Journal • Targeted Protein Degradation

Covalent Destabilizing Degrader of AR and AR-V7 in Androgen-Independent Prostate Cancer Cells. (PubMed, bioRxiv) - "Consistent with targeting both AR and AR-V7, we find that EN1441 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. Our results put forth a pathfinder molecule EN1441 that targets an intrinsically disordered cysteine within AR to destabilize, degrade, and inhibit both AR and AR-V7 in androgen-independent prostate cancer cells and highlights the utility of covalent ligand discovery approaches in directly targeting, destabilizing, inhibiting, and degrading classically undruggable transcription factor targets."

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

Rapid and high-throughput screening of proteolysis targeting chimeras using a dual-reporter system expressing fluorescence protein and luciferase. (PubMed, BMC Biol) - "The dual-reporter system using both fluorescence and chemiluminescence was successfully constructed. Using this method, we identified effective candidate PROTACs against SIRT2. The dual-reporter system may accelerate drug discovery during PROTAC development."

Journal • Targeted Protein Degradation • SIRT2

Circulating tumor cell RNA biomarker for bavdegalutamide (ARV-110) in metastatic castration-resistant prostate cancer without AR T878/H875 mutations. (ASCO-GU 2025) - "Pre-treatment CTCm score 6 months in this small study mCRPC patients without AR T878/H875 mutations. Further investigation of the CTCm biomarker is warranted in mCRPC patients treated with bavdegalutamide and potentially other AR PROTACs."

Biomarker • Circulating tumor cells • Metastases • Tumor cell • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AGR2 • FAT1 • FOLH1 • HOXB13 • KLK2 • KLK3 • STEAP2

ARDENT: Trial of ARV-110 in Patients With Metastatic Castration Resistant Prostate Cancer (clinicaltrials.gov) - P1/2 | N=250 | Active, not recruiting | Sponsor: Arvinas Inc. | Trial primary completion date: Apr 2024 ➔ Jan 2025

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

Unleashing the Power of Covalent Drugs for Protein Degradation. (PubMed, Med Res Rev) - "Two prominent PROTACs, ARV-471 and ARV-110, are currently undergoing phase III and II clinical trials, respectively. The concept of covalent degradation has also been utilized in various new forms of degraders, including covalent molecule glue (MG), in-cell click-formed proteolysis targeting chimera (CLIPTAC), HaloPROTAC, lysosome-targeting chimera (LYTAC) and GlueTAC. This review focuses on recent advancements in covalent degraders beyond covalent PROTACs and examines obstacles and future directions pertinent to this field."

Journal • Review • Oncology • Solid Tumor • Targeted Protein Degradation • BTK • DDB1 • EGFR • KEAP1 • KRAS

Preclinical Evaluation of Bavdegalutamide (ARV-110), a Novel PROteolysis TArgeting Chimera Androgen Receptor Degrader. (PubMed, Mol Cancer Ther) - P1/2 | "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)."

Journal • Preclinical • Castration-Resistant Prostate Cancer • Castration-Sensitive Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • AR • CRBN

Anti-tumor efficacy of ADT in combination with AR targeted therapies and anti-PD-1 is limited by regulatory T cells in murine prostate models (SITC 2024) - "In vivo experiments involved combining ADT with AR-targeted vaccination and either enzalutamide or ARV110 with anti-PD-1 in murine prostate tumor models. While the addition of PD-1 blockade to this combination showed only modest benefits, it led to an increase in intratumoral regulatory CD4+T cells, suggesting a complex interplay between immune activation and regulation with combination therapies. Overall, our study provides valuable insights into optimizing therapeutic strategies for prostate cancer treatment."

Combination therapy • IO biomarker • Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD4 • CD8

Anti-tumor efficacy of ADT in combination with AR targeted therapies and anti-PD-1 is limited by regulatory T cells in murine prostate models (SITC 2024) - "In vivo experiments involved combining ADT with AR-targeted vaccination and either enzalutamide or ARV110 with anti-PD-1 in murine prostate tumor models. While the addition of PD-1 blockade to this combination showed only modest benefits, it led to an increase in intratumoral regulatory CD4+T cells, suggesting a complex interplay between immune activation and regulation with combination therapies. Overall, our study provides valuable insights into optimizing therapeutic strategies for prostate cancer treatment."

Combination therapy • IO biomarker • Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD4 • CD8

Molecular properties, including chameleonicity, as essential tools for designing the next generation of oral beyond rule of five drugs. (PubMed, ADMET DMPK) - "Molecular descriptors of ARV-110, ARV-471, and DT-2216 are reported and the main limitations of the applied experimental approaches are discussed. Moreover, a simple computational method shows how predicting the presence of chameleonic effects. A full complete physicochemical characterization of three degraders in clinical trials is reported to highlight the differences in physicochemical descriptors between PROTACs dosed orally and intravenously."

Journal • Targeted Protein Degradation

Developing novel AR mutant prostate cancer models for CRPC related drug discovery (EORTC-NCI-AACR 2024) - "The modified cell line exhibited resistance to enzalutamide but remained sensitive to target protein degraders (TPDs), such as ARV-766, both in vitro and in vivo...Consistent with the preclinical studies previously reported, AR degraders (ARV-110 and ARV-766) are able to degrade these two clinically relevant mutant AR proteins and induce cell death. In summary, we present three engineered LNCaP prostate cancer models with certain AR hot spot mutations, T878A/F877L, T878S and T878A/H875Y. Their differential responses to AR antagonists or new drug modalities not only provide indications for the understanding of hormonal treatment resistance mechanism but also have implications for clinical utilization."

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

Discovery of Androgen Metabolism Enhancing Androgen Receptor Antagonists for the Treatment of Castration-Resistant prostate Cancer (EORTC-NCI-AACR 2024) - "To provide sustained treatment options, next-generation ARSIs with unique mechanisms of action, including our AR N terminus domain (NTD) binding degrader (SARD), ONCT-534, and PROTAC ARV-110 are in clinical development...Transcriptomic analysis with a combination of 19B and enzalutamide showed regulation of pathways that are distinct from that of enzalutamide. The results indicate that UGT2B enzyme expression and function are critical for the efficacy of AR antagonists. We have also discovered a new class of AR antagonist that sustainedly induces UGT2Bs and synergizes with clinical AR antagonists to inhibit PCa and CRPC growth."

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

Investigating the distinct phase separation properties of androgen receptor isoforms in prostate cancer (PCF 2024) - "To assess the role of chromatin accessibility, we used PROTAC AU15330 to degrade the ATPases SMARCA2/4 of the SWI/SNF complex and evaluate their role in AR-V7 condensate formation. We also evaluated the interdependency between AR-FL and AR-V7 condensates by using ARV-110, a degrader of AR-FL, in PCa models...Conclusions AR-V7 forms phase-separated condensates that are crucial for transcriptional regulation in PCa, distinguishing its role from that of AR-FL. By identifying AR-V7 condensate-dependent programs, we can gain insights into androgen-independent pathways that may be explored for future drug targeting, offering potential new therapeutic strategies for managing aggressive PCa subtypes."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • KRAS • MBD4 • MED1 • SMARCA2

Stability Evaluation and Pharmacokinetic Profiling of Vepdegestrant in Rodents Using Liquid Chromatography-Tandem Mass Spectrometry. (PubMed, Molecules) - "We developed and validated a sensitive and rapid liquid chromatography-tandem mass spectrometry method to quantify vepdegestrant in rodent plasma using bavdegalutamide (formerly ARV-110) as an internal standard. In liver microsomes, vepdegestrant exhibited moderate stability in rats but was stable in mice, dogs, and humans. These findings enhance the understanding of pharmacokinetic properties of vepdegestrant supporting further development of PROTAC drugs."

Journal • PK/PD data • Preclinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ER

Arvinas Reports Second Quarter 2024 Financial Results and Provides Corporate Update (GlobeNewswire) - "Research and development expenses were $93.7 million for the quarter ended June 30, 2024, as compared with $103.4 million for the quarter ended June 30, 2023. The decrease in research and development expenses of $9.7 million for the quarter was primarily due to decreases in expenses related to our ER program (which includes the cost sharing of vepdegestrant under the Vepdegestrant (ARV-471) Collaboration Agreement with Pfizer) of $6.6 million and our platform and exploratory programs of $5.7 million, partially offset by an increase in our AR program (which includes ARV-766 and bavdegalutamide (ARV-110)) of $2.6 million. Revenues were $76.5 million for the quarter ended June 30, 2024, as compared with $54.5 million for the quarter ended June 30, 2023."

Commercial • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer • Oncology

Radioactive ADME Demonstrates ARV-110's High Druggability Despite Low Oral Bioavailability. (PubMed, J Med Chem) - "However, the therapeutic effect of ARV-110 at a low dose was much better than that of enzalutamide, demonstrating the specific catalytic medicinal properties of PROTACs. Notably, the specificity and activity of PROTACs take precedence over their oral absorption, and high oral bioavailability is not necessary to produce excellent therapeutic effects. This work presents a roadmap for developing future PROTAC medications from a radioactive drug metabolism and pharmacokinetics (DMPK) perspective."

Journal • Oncology • Prostate Cancer • Targeted Protein Degradation

Use of Poly(vinyl alcohol) in Spray-Dried Dispersions: Enhancing Solubility and Stability of Proteolysis Targeting Chimeras. (PubMed, Pharmaceutics) - "In this study, we show the solubility enhancement of two PROTACs, ARV-110 and SelDeg51, using Poly(vinyl alcohol)...Additionally, activity studies and binding assays of the pure SelDeg51 versus the spray-dried SelDeg51-PVA indicate no difference between both samples. Our results show how modern enabling formulation technologies can partially alleviate challenging physicochemical properties, such as the poor solubility of increasingly large 'small' molecules."

Journal • Inflammatory Arthritis • Targeted Protein Degradation

PROTAC'ing the androgen receptor and other emerging therapeutics in prostate cancer. (PubMed, Expert Rev Anticancer Ther) - "PROTACs, DAARIs, and anitens represent novel and promising AR-targeting therapeutics that may become an important part of prostate cancer treatment in the future. Elucidating mechanisms of resistance, including ability of these agents to target full length AR, may yield further insights into maximal therapeutic efficacy aimed at silencing AR signaling."

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

Development and validation of LC-MS/MS methods for the pharmacokinetic assessment of the PROTACs bavdeglutamide (ARV-110) and vepdegestrant (ARV-471). (PubMed, J Pharm Biomed Anal) - "The plasma concentration-time curves after intravenous and intraduodenal bolus single-dose administrations in rats could be successfully quantified at clinically relevant doses per body weight. The highly sensitive bioanalytical assays presented in this work enable the application of a broad spectrum of in vivo studies to elucidate the oral absorption, bioavailability, and disposition of PROTACs."

Journal • PK/PD data • Targeted Protein Degradation

UBX-390: A Novel Androgen Receptor Degrader for Therapeutic Intervention in Prostate Cancer. (PubMed, Adv Sci (Weinh)) - "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."

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