ASCO20: Phase I Trial of ARV-110 for Metastatic Castration-Resistant Prostate Cancer
Posted: Friday, June 19, 2020
According to Daniel Peter Petrylak, MD, of the Smilow Cancer Center, Yale University, New Haven, Connecticut, and colleagues, ARV-110 may demonstrate antitumor activity in patients with metastatic castration-resistant prostate cancer after enzalutamide/abiraterone therapy. However, further investigation into the maximum tolerated dose and recommended phase II dose of this proteolysis-targeting chimera (PROTAC) protein degrader is warranted. The results of this first-in-human phase I trial were presented during the ASCO20 Virtual Scientific Program (Abstract 3500).
“PROTAC protein degraders induce selective degradation of targeted proteins by engaging the ubiquitin proteasome system,” the investigators commented. “ARV-110 is an orally bioavailable PROTAC that specifically degrades androgen receptors [by at least] 95% and achieves antitumor activity in enzalutamide-naive and -resistant prostate cancer xenograft models.”
A total of 18 patients with metastatic castration-resistant prostate cancer who previously received at least two anticancer therapies participated in the study. Prior to enrollment, 12 patients underwent enzalutamide and abiraterone therapy, and 14 underwent chemotherapy. The patients were stratified into four ARV-110 dosing groups: 35 mg (n = 3), 70 mg (n = 4), 140 mg (n = 8), and 280 mg (n = 3).
Grade 4 elevated aspartate transaminase/alanine transaminase (AST/ALT) and acute renal failure were observed in one patient in the 280-mg dosing group who was concurrently taking rosuvastatin. A second patient taking rosuvastatin experienced a grade 3 elevation in AST/ALT. Concurrent rosuvastatin therapy was subsequently prohibited.
The pharmacokinetic profile of ARV-110 was reported to be dose‐proportional. At 140 mg, ARV-110 appeared to demonstrate preclinical antitumor activity. Of the 15 patients evaluable for prostate-specific antigen response, 2 patients in the 140-mg dosing group achieved confirmed declines of more than 50%. Both patients were previously treated with enzalutamide and abiraterone, chemotherapy, bicalutamide, and radium-223. The first patient had two androgen receptor mutations associated with enzalutamide resistance. According to the investigators, the second patient experienced an unconfirmed partial response.
Disclosure: For full disclosures of the study authors, visit coi.asco.org.
