PROSTATE CANCER: A PROTAC-based androgen receptor degrader has shown anti-tumour activity in first in human studies presented at ASCO.

PROTAC-based therapeutics represent a novel approach to treatment that has the potential to impact a number of cancer indications.


Daniel Peter Petrylak at al ASCO Meeting Library


Proteolysis Targeting Chimera (PROTAC) protein degraders induce selective degradation of targeted proteins by engaging the ubiquitin proteasome system. ARV-110 is an orally bioavailable PROTAC that specifically degrades AR ≥ 95% and achieves anti-tumor activity in ENZ-naïve and -resistant prostate cancer xenograft models.


To define the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ARV-110, pts with ≥ 2 prior therapies for mCRPC, including ENZ and/or ABI, received ARV-110 orally once daily. Dose escalation is per 3+3 design. Endpoints include dose limiting toxicities (DLTs), adverse events (AEs), pharmacokinetics (PK), biomarkers (e.g., AR mutation analysis), RECIST and PSA response.


By January 2020, 18 pts were dosed: 35 mg (N = 3), 70 mg (N = 4), 140 mg (N = 8), 280 mg (N = 3). 12 pts received both ENZ and ABI; 14 received prior chemotherapy. 1 of 18 pts experienced a DLT (280 mg) of Grade (Gr) 4 elevated AST/ALT followed by acute renal failure while taking rosuvastatin (ROS). A 2nd pt had Gr 3 AST/ALT with ROS that resolved off ROS, permitting ARV-110 retreatment. ROS plasma concentrations demonstrated significant increases concurrent with AST/ALT elevations in both pts. Subsequently, ROS was prohibited without further ≥Gr 2 AST/ALT AEs. No other related Gr 3/4 AEs were reported. ARV-110 PK was generally dose proportional and at 140 mg reached levels associated with preclinical anti-tumor activity. 15 pts were evaluable for PSA response (excludes 1 pt stopped after 1 dose for early progression and 2 pts initiated 2 weeks before cutoff, all at 140 mg). Of these, 8 pts initiated dosing at ≥140 mg. 2 pts achieved confirmed PSA declines of >50%, both at 140 mg. Prior therapy in both pts included ENZ and ABI, chemotherapy, bicalutamide and radium-223 plus other regimens. 1 pt had 2 AR mutations known to confer ENZ resistance. The 2nd pt also achieved an unconfirmed RECIST partial response (confirmatory scan pending). Both responses were ongoing at data cutoff (8+ and 21+ weeks of treatment).


To date, ARV-110 has an acceptable safety profile. Concurrent ROS is now prohibited. MTD has not yet been established; determination of RP2D continues. ARV-110 demonstrates antitumor activity in mCRPC after ENZ/ABI with 2 ongoing confirmed PSA responses, one of which was associated with tumor reduction. Updated data for this first PROTAC in clinical testing will be presented. Clinical trial information: NCT03888612.

You may also be interested in these resources

Scientific Application Note

LUNG CANCER: Data from TRACERx presented at AACR provides further support for the use of personalised ctDNA assays in the assessment of minimal residual disease and impending progression following surgery for early stage disease

CT023 – Phylogenetic tracking and minimal residual disease detection using ctDNA in early-stage NSCLC: A lung TRACERx study AACR Annual Meeting 2020 Online Proceedings and Itinerary Planner Home April 28, 2020 ABSTRACT INTRODUCTION  Minimal residual disease...

Share This