Cited by 169Prostate Cancer Treatment and ResearchProtein Degradation and InhibitorsLung Cancer Treatments and Mutations

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First-in-human phase I study of ARV-110, an androgen receptor (AR) PROTAC degrader in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) following enzalutamide (ENZ) and/or abiraterone (ABI).

Petrylak, Daniel Peter, Gao, Xin, Vogelzang, Nicholas J., Garfield, Mary Harlow, Taylor, Ian, Dougan Moore, Marcia, Peck, Ronald Alan, Burris, Howard A.·2020·Journal of Clinical Oncology

DOI 10.1200/jco.2020.38.15_suppl.3500

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Abstract

3500 Background: Proteolysis Targeting Chimera (PROTAC) protein degraders induce selective degradation of targeted proteins by engaging the ubiquitin proteasome system. ARV-110 is an orally bioavailable PROTAC that specifically degrades AR ≥ 95% and achieves anti-tumor activity in ENZ-naïve and -resistant prostate cancer xenograft models. Methods: To define the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ARV-110, pts with ≥ 2 prior therapies for mCRPC, including ENZ and/or ABI, received ARV-110 orally once daily. Dose escalation is per 3+3 design. Endpoints include dose limiting toxicities (DLTs), adverse events (AEs), pharmacokinetics (PK), biomarkers (e.g., AR mutation analysis), RECIST and PSA response. Results: By January 2020, 18 pts were dosed: 35 mg (N = 3), 70 mg (N = 4), 140 mg (N = 8), 280 mg (N = 3). 12 pts received both ENZ and ABI; 14 received prior chemotherapy. 1 of 18 pts experienced a DLT (280 mg) of Grade (Gr) 4 elevated AST/ALT followed by acute renal failure while taking rosuvastatin (ROS). A 2 nd pt had Gr 3 AST/ALT with ROS that resolved off ROS, permitting ARV-110 retreatment. ROS plasma concentrations demonstrated significant increases concurrent with AST/ALT elevations in both pts. Subsequently, ROS was prohibited without further ≥Gr 2 AST/ALT AEs. No other related Gr 3/4 AEs were reported. ARV-110 PK was generally dose proportional and at 140 mg reached levels associated with preclinical anti-tumor activity. 15 pts were evaluable for PSA response (excludes 1 pt stopped after 1 dose for early progression and 2 pts initiated 2 weeks before cutoff, all at 140 mg). Of these, 8 pts initiated dosing at ≥140 mg. 2 pts achieved confirmed PSA declines of >50%, both at 140 mg. Prior therapy in both pts included ENZ and ABI, chemotherapy, bicalutamide and radium-223 plus other regimens. 1 pt had 2 AR mutations known to confer ENZ resistance. The 2nd pt also achieved an unconfirmed RECIST partial response (confirmatory scan pending). Both responses were ongoing at data cutoff (8+ and 21+ weeks of treatment). Conclusions: To date, ARV-110 has an acceptable safety profile. Concurrent ROS is now prohibited. MTD has not yet been established; determination of RP2D continues. ARV-110 demonstrates antitumor activity in mCRPC after ENZ/ABI with 2 ongoing confirmed PSA responses, one of which was associated with tumor reduction. Updated data for this first PROTAC in clinical testing will be presented. Clinical trial information: NCT03888612 .

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McAnulty, J., & DiFeo, A. V. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21249486 · Cited by 28
“PROTAC technology has entered clinical trials, including Arvinas’s ARV-110 for patients with metastatic castration-resistant prostate cancer (NCT03888612) which has shown efficacy and a promising safety profile in Phase I [75].”
Method
Androgen Receptor Signaling Inhibition in Advanced Castration Resistance Prostate Cancer: What Is Expected for the Near Future?
Pozas, J., Rodríguez, S. Á., Albarrán, V., Burgos, J., Santoni, M., Kopp, R. M., Molina‐Cerrillo, J., & Alonso‐Gordoa, T. (2022) · Cancers · doi:10.3390/cancers14246071 · Cited by 28
Early evaluation of opportunities in oral delivery of PROTACs to overcome their molecular challenges
Yang, W., Saboo, S., Zhou, L., Askin, S., & Bak, A. (2023) · Drug Discovery Today · doi:10.1016/j.drudis.2023.103865 · Cited by 24
Discovery of ZLC491 as a Potent, Selective, and Orally Bioavailable CDK12/13 PROTAC Degrader
Zhou, L., Zhou, K., Chang, Y., Yang, J., Fan, B., Su, Y., Li, Z., Mannan, R., Mahapatra, S., Ding, M., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c01596 · Cited by 26
Navigating PROTACs in Cancer Therapy: Advancements, Challenges, and Future Horizons
Ibrahim, S., Khan, M. U., Khurram, I., Rehman, R., Rauf, A., Ahmad, Z., Aljohani, A. S. M., Abdulmonem, W. A., & Quradha, M. M. (2025) · Food Science & Nutrition · doi:10.1002/fsn3.70011 · Cited by 27
SPOP-mutant prostate cancer: Translating fundamental biology into patient care
Bernasocchi, T., & Theurillat, J.-P. P. (2021) · Cancer Letters · doi:10.1016/j.canlet.2021.12.024 · Cited by 22
Proteolysis-Targeting Chimera (PROTAC): Is the Technology Looking at the Treatment of Brain Tumors?
Severini, L. L., Bufalieri, F., Infante, P., & Marcotullio, L. D. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.854352 · Cited by 23
Research Advances in Chaperone-Mediated Autophagy (CMA) and CMA-Based Protein Degraders
Pan, Z., Huang, X., Liu, M., Jiang, X. L., & He, G. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c02681 · Cited by 21
KIT/PDGFRA inhibitors for the treatment of gastrointestinal stromal tumors: getting to the gist of the problem
Cicala, C. M., Olivares-Rivas, I., Aguirre-Carrillo, J. A., et al. (2024) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2024.2318317 · Cited by 19
“PROTACs are available as oral molecules; the first signals of activity of PROTACs in patients have been recently described in a study conducted in patients with prostate cancer, in which the androgen receptor (AR) acted as the targeted protein [74,75].”
Background
Novel hormone therapies for advanced prostate cancer: Understanding and countering drug resistance
Wang, Z., Wang, J., Li, D., Wu, R., Huang, J., Ye, L., Tuo, Z., Yu, Q., Shao, F., Wusiman, D., et al. (2025) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2025.101232 · Cited by 20
Targeted Protein Degradation in Cancer: PROTACs, New Targets, and Clinical Mechanisms
Faryal, B., Abideen, Z. U., Irfan, M., Ahmed, H., Jalilov, F. S., Abduraximova, L., & Ashraf, G. A. (2026) · Biomolecules · doi:10.3390/biom16020325 · Cited by 24
“In heavily pre-treated mCRPC patients, ARV-110 showed a favorable safety pro-ﬁle and dose-proportional pharmacokinetics, supporting a recommended dose of 420 mg administered once daily [62].”
Huntingtin Ubiquitination Mechanisms and Novel Possible Therapies to Decrease the Toxic Effects of Mutated Huntingtin
Fiorillo, A., Morea, V., Colotti, G., & Ilari, A. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11121309 · Cited by 19
Bayesian optimization for ternary complex prediction (BOTCP)
Rao, A., Tunjic, T. M., Brunsteiner, M., Müller, M., Fooladi, H., Gasbarri, C., & Weber, N. (2023) · Artificial Intelligence in the Life Sciences · doi:10.1016/j.ailsci.2023.100072 · Cited by 25
Design, Synthesis, and Biological Evaluation of Androgen Receptor (AR) Antagonist-Heat Shock Protein 90 (Hsp90) Inhibitor Conjugates for Targeted Therapy of Castration-Resistant Prostate Cancer
Zhang, S., Meng, X.-L., Zhang, S., Li, B., Jin, W., Zhang, C., Liu, Z., Hu, X., Ge, L., Yu, Z., et al. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01970 · Cited by 20
Regulation of eDHFR-tagged proteins with trimethoprim PROTACs
Etersque, J. M., Lee, I. K., Sharma, N., Xu, K., Ruff, A., Northrup, J. D., Sarkar, S., Nguyen, T., Lauman, R., Burslem, G. M., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-42820-3 · Cited by 17
“ARV-110 and ARV-471 target endogenous proteins and have shown promise in clinical trials for prostate and breast cancer, respectively 17,18 .”
Discovery of the first ataxia telangiectasia and Rad3-related (ATR) degraders for cancer treatment
Huang, L. H., Shao, J., Lai, W., Gu, H., Yang, J., Shi, S., Wufoyrwoth, S., Song, Z., Zou, Y., Xu, Y., et al. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116159 · Cited by 16
Small-Molecule Approaches to Target Transcription Factors
Cui, H., Stilgenbauer, M., & Koehler, A. N. (2024) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-062722-012209 · Cited by 19
The emerging role of targeted protein degradation to treat and study cancer
Brodermann, M. H., Henderson, E. K., & Sellar, R. S. (2024) · The Journal of Pathology · doi:10.1002/path.6301 · Cited by 15
Kidney Cancer and Chronic Kidney Disease: Too Close for Comfort
Caetano-Pinto, P., Rönnau, C., Burchardt, M., & Wolff, I. (2021) · Biomedicines · doi:10.3390/biomedicines9121761 · Cited by 17
“This is illustrated by the development of ARV-110, an androgen receptor degrader currently undergoing phase II trials (NCT03888612) for the treatment of castration resistant prostate cancer [88].”
Method
Precision Targets for Intercepting the Lethal Progression of Prostate Cancer: Potential Avenues for Personalized Therapy
Christenson, M., Song, C. S., Liu, Y., & Chatterjee, B. (2022) · Cancers · doi:10.3390/cancers14040892 · Cited by 15
“Responding tumors harbor AR mutations that lead to ARAT resistance [92].”
Background
Emerging therapies to overcome antiandrogen resistance and beyond in lethal prostate cancer
Huang, F., Li, K., Shevach, J. W., & Wang, Q. (2025) · Journal of the National Cancer Center · doi:10.1016/j.jncc.2025.04.004 · Cited by 18
Next-generation cancer therapeutics: PROTACs and the role of heterocyclic warheads in targeting resistance
Omar, E. A., Rajesh, R., Das, P. K., Pal, R., Matada, G. S. P., & Maji, L. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.117034 · Cited by 14
Stimulation of antitumor immunity by FoxP3-targeting PROTAC
Wang, Y., Zhang, Y., Su, S., et al. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114871 · Cited by 12
Targeting Oncoproteins for Degradation by Small Molecule-Based Proteolysis-Targeting Chimeras (PROTACs) in Sex Hormone-Dependent Cancers
Liu, L., Shi, L., Wang, Z., Zeng, J., Wang, Y., Xiao, H., & Zhu, Y. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.839857 · Cited by 13
Selectively Targeting Tropomyosin Receptor Kinase A (TRKA) via PROTACs
Xiang, W., & Wang, S. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01947 · Cited by 12
New approaches for challenging therapeutic targets
Sharma, K. R., Malik, A., Roof, R. A., Boyce, J. P., & Verma, S. K. (2024) · Drug Discovery Today · doi:10.1016/j.drudis.2024.103942 · Cited by 16
Precision oncology revolution: CRISPR-Cas9 and PROTAC technologies unleashed
Kanbar, K., Darzi, R. E., & Jaalouk, D. E. (2024) · Frontiers in Genetics · doi:10.3389/fgene.2024.1434002 · Cited by 17

Authors: Petrylak, D. P., Gao, X., Vogelzang, N. J., Garfield, M. H., Taylor, I., Dougan Moore, M., Peck, R. A., & Burris, H. A.
Affiliations: Yale University (US)
Massachusetts General Hospital (US)
Comprehensive Cancer Centers of Nevada (US)
Arvinas (United States) (US)
Arvinas, Inc, New Haven, CT;
Sarah Cannon (US)
ORCID: Petrylak, Daniel Peter
Gao, Xin
Vogelzang, Nicholas J.
Burris, Howard A.
Venue: Journal of Clinical Oncology
Publisher: American Society of Clinical Oncology (ASCO)
Published: 2020-05-20
Volume: 38
Issue: 15_suppl
Pages: 3500-3500
ISSN: 0732-183X (ISSN-L)
1527-7755
DOI: 10.1200/jco.2020.38.15_suppl.3500
OpenAlex: W3031756382
Cited by: 169
References: 0
Citations by year: 2026: 14 · 2025: 24 · 2024: 31 · 2023: 23 · 2022: 38 · 2021: 30 · 2020: 9
Type: conference abstract
Language: en
Open access: closed
Locations: Journal of Clinical Oncology (publishedVersion)
Funders: Arvinas
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Prostate Cancer Treatment and Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords: PROTAC degraders, androgen receptor degradation, metastatic castration-resistant prostate cancer, enzalutamide, abiraterone, maximum tolerated dose, dose-limiting toxicity, rosuvastatin, hepatotoxicity, pharmacokinetics, PSA response, androgen receptor mutations, dose escalation, treatment-emergent adverse events

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First-in-human phase I study of ARV-110, an androgen receptor (AR) PROTAC degrader in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) following enzalutamide (ENZ) and/or abiraterone (ABI).

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