PROTACs (proteolysis targeting chimera) facilitate the tagging of a target protein with ubiquitin molecules by enzymes called E3 ubiquitin ligases, which then lead to the target protein being shuttled to and degraded by the proteasome. A PROTAC consists of (1) a protein ligand domain that targets the protein of interest, (2) a linker region that serves to properly orient the target protein and the E3 ubiquitin ligase, and (3) a ligase ligand which recruits a specific E3 ubiquitin ligase. Each PROTAC molecule is capable of causing the degradation of up to 200 target protein molecules.
ARV-110 is a first-in-class PROTAC that effectively targets the wild type Androgen Receptor (AR) and certain genomic alterations of the AR (amplification, T878A, H875Y, F877L, M895V, but not L702H or AR-V7) for degradation in both enzalutamide sensitive and resistant preclinical models.
In this presentation, Daniel Petrylak, MD, and colleagues present results from a first-in-human phase I study of ARV-110 in patients with metastatic castration-resistant prostate cancer (mCRPC) who experienced rising PSA or 2+ new lesions on bone scan after at least two prior systemic therapies, one of which was abiraterone or enzalutamide. The primary endpoint was to define the maximum tolerated dose in order to recommend a phase 2 treatment dose. The secondary endpoints were pharmacokinetics and anti-tumor activity (PSA50, RECIST). Exploratory biomarker analyses planned include ctDNA mutational profiling, AR protein levels in paired biopsies when available, and circulating tumor cell measurement of AR and AR-V7 levels.
Baseline patient characteristics are shown below:
The number of treatment-associated adverse events increased as expected with dose. Notably, grade 3 or greater effects were limited to transaminitis and renal failure. Regarding transaminitis, a possible interaction was established between rosuvastatin and ARV-110. No transaminitis was seen after a rosuvastatin restriction was implemented. No other statin was associated with transaminitis while on ARV-110 therapy.
Doses of 140 mg daily or higher were sufficient to achieve the level of ARV-110 that led to tumor growth inhibition in preclinical molecules. There is preliminary evidence from limited samples that AR protein levels decreased substantially with ARV-110 treatment. Half of patients remain on therapy. PSA response data and AR genomic status summary results are shown below.
Two patients had PSA50 responses, one of whom had confirmed radiographic response by RECIST criteria. Importantly, the responders had evidence of AR mutations that cause resistance to anti-AR therapies.
In summary, the first-in-class PROTAC ARV-110 has clinical activity in pre-treated mCRPC patients who have progressed on anti-androgen therapy. Available safety data support further dose escalation, and a phase 2 cohort is planned once the recommended phase 2 dose is determined.
Presented by: Daniel Petrylak, MD, Professor of Medicine and Urology, Yale School of Medicine, New Haven, CT
Written by: Alok Tewari, MD, PhD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2020 American Society of Clinical Oncology virtual annual meeting (#ASCO20), May 29th-May 31st, 2020