Dr Yu on the Evolving Role of AR Inhibitors and Degraders in Metastatic Prostate Cancer

“Just degrading the AR [mutations] may be efficacious… That’s something that I think [we should] keep an eye out for… It might actually lead to more serial circulating tumor DNA testing to try to identify these resistance mutations that can occur in response to prolonged treatment with AR pathway inhibitors.”

Evan Y. Yu, MD, section head of Medical Oncology and a professor in the Clinical Research Division at the Fred Hutchinson Cancer Center; medical director of Clinical Research Support at Fred Hutchinson/University of Washington (UW)/Seattle Children’s Cancer Consortium; and the assistant fellowship director and a professor in the Division of Hematology and Oncology at UW Medicine, discussed the development of androgen receptor (AR)–targeted therapies for patients with metastatic prostate cancer.

Two promising therapeutic approaches under investigation for patients with prostate cancer involve AR degraders and the novel agent opevesostat, Yu began. AR degraders function by targeting the AR protein for proteasomal degradation, reducing receptor activity and potentially overcoming resistance mechanisms associated with AR mutations, he said.

Opevesostat acts upstream of CYP17A by inhibiting CYP11A1, Yu explained. This mechanism leads to the complete suppression of adrenal steroid hormone production, including glucocorticoids, estrogens, and mineralocorticoids, according to Yu. Due to this broad suppression, steroid replacement therapy, such as dexamethasone for glucocorticoid support and fludrocortisone for mineralocorticoid replacement, is required, he emphasized. This agent may be beneficial in patients harboring AR mutations, where alternative steroid hormones could aberrantly activate mutant AR pathways, driving disease progression, he noted. By fully abrogating steroid hormone synthesis, opevesostat may mitigate this risk and provide a novel treatment avenue, he reported.

Additionally, targeting AR degradation itself may serve as an effective strategy to counteract treatment resistance in patients with AR mutations, Yu said. These emerging treatments may necessitate increased use of serial circulating tumor DNA testing to detect resistance mutations that develop in response to prolonged AR pathway inhibition, he concluded.