A drug that turns cells’ protein recycling machinery against advanced prostate cancer reduced tumor activity and pain in an early clinical trial, suggesting a possible way around resistance to hormone therapy.
Prostate cancer treatments often work by depriving tumors of testosterone, a hormone that helps drive their growth. That approach can hold the disease in check for a time. In metastatic castration-resistant prostate cancer, or mCRPC, the cancer has spread beyond the prostate and continues growing even with little testosterone available. This form of the disease is incurable and lethal.
“More than 35,000 men will die from mCRPC in the United States this year,” says Daniel Petrylak, MD, professor of medicine (oncology and hematology) at Yale School of Medicine and a member of Yale Cancer Center. “It’s the most advanced form of prostate cancer.”
Tumor shrinkage and pain relief
A Yale-led clinical trial tested a drug designed to bypass that resistance by targeting androgen receptors, the proteins through which testosterone helps control prostate cancer growth. Called bavdegalutamide, or ARV-110, the drug showed promising results in patients who had already received treatment for mCRPC, including reductions in tumor activity and pain. Petrylak was the senior author of the study, published Oct. 9 in the Journal of Clinical Oncology.
The Phase I/Phase II trial first addressed dosing and safety, then evaluated effectiveness. In Phase I, the researchers found that a daily dose of 420 milligrams was safe in the patients studied. For Phase II, the team measured prostate-specific antigen, or PSA, before and after treatment to assess changes in disease activity.
“There was a decrease in prostate-specific androgen. We also saw regressions in soft tissue lesions, and improvements in pain,” says Petrylak. “These are the parameters that indicate a positive response.”
The responses also varied with the cancer’s genetic characteristics. Patients whose cancers carried androgen receptor mutations known as T878 and/or H875 had greater reductions in PSA. The study’s authors saw this finding as evidence of the potential for PROTAC drugs, the class that includes bavdegalutamide, to serve as precision medicines, with treatment tailored to the molecular features of a patient’s cancer.
Breaking down prostate cancer’s testosterone receptors
Rather than simply limiting the testosterone available to a tumor, bavdegalutamide removes the receptors that respond to it. It is the first PROTAC androgen receptor degrader to be tested clinically. PROTACs are a new class of cancer drugs that harness proteolysis, the normal process by which cells break down proteins and recycle their components.
“Bavdegalutamide takes your own natural protein degradation system, and it accelerates the process for the androgen receptor. The drug degrades the receptors for testosterone, which control prostate cancer growth,” says Petrylak.
Yale researcher Craig Crews, PhD, pioneered PROTACs, including the first PROTAC approved by the U.S. Food and Drug Administration for use in breast cancer. The bavdegalutamide trial brought that approach into clinical testing against prostate cancer.
“This is a first-in-class drug for prostate cancer,” says Petrylak.
The researchers and their clinical collaborators are now testing a second PROTAC, called ARV-766, in Phase I and Phase II trials. It is active against a broader range of androgen receptor mutations than ARV-110.
Reference: “Phase I/II Study of Bavdegalutamide, a Proteolysis-Targeting Chimera Androgen Receptor Degrader, in Metastatic Castration-Resistant Prostate Cancer” by Xin Gao, Benjamin Garmezy, Jacqueline Vuky, John Shen, Oliver Sartor, Cora N. Sternberg, Robert Dreicer, Maha Hussain, Arash Rezazadeh Kalebasty, Ivor J. Percent, Elisabeth I. Heath, Sunil Gandhi, Benjamin L. Maughan, Xin Zhi, Sean Landrette, Jiachang Gong, Diane Healey, Janaki Parameswaran and Daniel P. Petrylak, 9 October 2026, Journal of Clinical Oncology.
DOI: 10.1200/JCO-25-02995
Supported by Arvinas Androgen Receptor, Inc.
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