FDA Grants Fast Track Designation to ARV-110 for mCRPC

John Houston, PhD

The FDA has granted a fast track designation to ARV-110, a PROTAC^® protein degrader, for use as a treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have disease progression following ≥2 systemic therapies.

The orally bioavailable ARV-110, which is designed to selectively target and degrade the androgen receptor (AR), is currently being investigated in a phase I trial (NCT03888612). Researchers are evaluating the pharmacokinetics, safety, and tolerability of the agent in this patient population who have already received standard regimens.

“While great strides have been made in the treatment of men with metastatic castration-resistant prostate cancer, current AR-targeted standard-of-care treatments are less effective in patients whose disease includes increased levels of androgen production or mutations in the androgen receptor,” John Houston, PhD, president and chief executive officer of Arvinas, Inc., the developer of ARV-110, in a press release. “We believe, due to its ability to iteratively degrade the AR protein, ARV-110 could represent a meaningful new therapy to improve the lives of patients battling mCRPC, and for whom current therapies are not effective. The Fast Track designation by the FDA recognizes the urgency for improved treatments for these patients.”

Currently available, standard-of-care AR-targeted regimens for patients with mCRPC are said to be less effective in those with disease that has increased levels of androgen production, AR gene or gene enhancer amplification, or AR point mutations. Approximately 15% to 25% of patients do not respond to second-generation hormone therapies, such as abiraterone acetate (Zytiga) and enzalutamide (Xtandi), and the majority of patients who do respond will eventually develop resistance.

PROTAC® protein degraders use an E3 ligase to tag the target protein with ubiquitin, which directs its degradation through the proteasome. As the target protein is degraded, the protein degrader is released and acts iteratively to destroy additional target protein. Preclinical data have demonstrated that ARV-110 has activity in models with AR mutations or overexpression.

In the ongoing, first-in-human, dose-escalation phase I study (NCT03888612), an estimated 36 patients with mCRPC who have progressed on ≥2 systemic therapies will receive ARV-110 orally once daily in 28-day cycles. To be eligible for enrollment, patients must be ≥18 years of age and have ongoing androgen deprivation therapy. Those with symptomatic brain metastases requiring the use of steroids, undergo major surgery and/or radiation therapy within 4 weeks of the first dose of treatment, or receive systemic anti-cancer therapy within 2 weeks of first dose of therapy are excluded from enrollment.

The primary endpoints of the study are incidence of dose-limiting toxicities, number of patients with adverse events, and incidence of laboratory abnormalities.

Preliminary findings for the phase I trial will be announced in the second half of 2019, which include safety, tolerability, and PK data, the company stated in the press release. Additionally, full disclosure of trial information is expected in the first half 2020, which will include prostate-specific antigen (PSA) data and RECIST data.

Arvinas Receives Fast Track Designation for its Targeted Protein Degrader ARV-110 as a Treatment for Men with Metastatic Castration-Resistant Prostate Cancer. Arvinas, Inc. Published May 29, 2019. https://bit.ly/2wrTs44. Accessed May 29, 2019.