A Promising New Targeted Therapy for Patients with Metastatic Prostate Cancer with Therapy-Resistant Mutations

Newswise —

Testosterone fuels the growth of prostate cancer. The target of testosterone is the androgen receptor. Metastatic prostate cancer is treated by reducing levels of testosterone, and despite initial responses to treatment, nearly all patients become resistant to androgen deprivation therapy. Further deprivation of testosterone or blocking the androgen receptor are two ways that further responses can be attained, but for most patients, resistance again ensues.

A phase 1/2 clinical study led by Yale Cancer Center (YCC) researchers at Yale School of Medicine has revealed promising results for ARV-766 or Proteolysis-targeting chimera (PROTAC), which is a new type of therapy designed to combat metastatic castration-resistant prostate cancer (mCRPC) by targeting protein degradation of the androgen receptor. It targets both the wild-type androgen receptor (AR) and clinically significant AR ligand-binding domain (LBD) mutations, which are known to contribute to the progression of the disease in 20-25% of men with mCRPC.

First author of the study Daniel Petrylak, MD, who is the chief of genitourinary oncology at Yale Cancer Center and Smilow Cancer Hospital, will present the study’s findings at the American Society Clinical Oncology annual meeting on June 3 in Chicago, Il.

“My excitement about ARV-766 stems from the fact that it's a drug which was generated out of laboratory work from Craig Crews at Yale,” said Dr. Petrylak, who is also a professor of medicine (medical oncology) and of urology at Yale School of Medicine. “The concept of targeting prostate cancer came from interaction between Craig and I at a multidisciplinary conference that was held between the chemistry department and Yale Cancer Center.”

The study demonstrated that ARV-766 has significant antitumor activity, with 43% of patients demonstrating a prostate-specific antigen (PSA) decline of at least 50% in the subgroup of patients with tumors that have AR LBD mutations. About 30% of patients had some form of soft tissue shrinkage and only 8% of the 123 patients experienced treatment adverse events that led to the discontinuation of the therapy.

“Our data demonstrate that ARV-766 has promising clinical activity in patients with ligand binding mutations and this represents a potential new type of targeted therapy for prostate cancer, warranting further development in resistant-disease,” said Dr. Petrylak. “Phase III studies are justified by this data.”