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).
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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Initial trial data showed that ARV-110 was well tolerated at doses up to 420 mg.
“Initial trial data showed that ARV-110 was well tolerated at doses up to 420 mg.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [40]
ARV-110 mediated degradation of the protein target in tumours - the first such evidence for a PROTAC molecule in humans.
“The data also demonstrated ARV-110-mediated degradation of the protein target in tumours — the first such evidence for a PROTAC molecule in humans — and revealed early signs of antitumour activity, as measured by reductions in levels of prostate specific antigen (PSA) and/or by RECIST (Response Evaluation Criteria in Solid Tumors).”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [40]
ARV-110 revealed early signs of antitumour activity, as measured by reductions in levels of prostate specific antigen (PSA) and/or by RECIST.
“The data also demonstrated ARV-110-mediated degradation of the protein target in tumours — the first such evidence for a PROTAC molecule in humans — and revealed early signs of antitumour activity, as measured by reductions in levels of prostate specific antigen (PSA) and/or by RECIST (Response Evaluation Criteria in Solid Tumors).”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [40]
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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 25 · see citing works
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 25 · see citing works
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 · see citing works
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 · see citing works
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 20 · see citing works
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 · see citing works
“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].”
BackgroundNovel 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 19 · see citing works
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 22 · see citing works
“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].”
Fiorillo, A., Morea, V., Colotti, G., & Ilari, A. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11121309 · Cited by 18 · see citing works
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 · see citing works
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 19 · see citing works
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 15 · see citing works
“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 · see citing works
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 16 · see citing works
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 · see citing works
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 16 · see citing works
“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].”
MethodChristenson, M., Song, C. S., Liu, Y., & Chatterjee, B. (2022) · Cancers · doi:10.3390/cancers14040892 · Cited by 15 · see citing works
“Responding tumors harbor AR mutations that lead to ARAT resistance [92].”
BackgroundEmerging 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 · see citing works
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 · see citing works
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 · see citing works
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 12 · see citing works
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 · see citing works
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 12 · see citing works
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 · see citing works
- 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)
- Venue
- Journal of Clinical Oncology
- Published
- 2020-05-20
- Volume
- 38
- Issue
- 15_suppl
- Pages
- 3500-3500
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- 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
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › 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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