MP14-19: ARV-766, a PROTAC androgen receptor (AR) degrader, combined with abiraterone in novel hormonal agent (NHA)-naïve metastatic prostate cancer: phase 1 cohort (part C) of a phase 1/2 study

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Author Block

Neal Shore, Myrtle Beach, SC, Joshua M Lang, Madison, WI, Daniel M Geynisman, Philadelphia, PA, Tyler F Stewart, San Diego, CA, Xin Gao, Boston, MA, Leonard J Appleman, Pittsburgh, PA, Robert Dreicer, Charlottesville, VA, Tanya Dorff, Duarte, CA, Elmer Berghorn, Elizabeth Duperret, Haolan Lu, Edward Chan, New Haven, CT, Benjamin Garmezy, Nashville, TN, Daniel P Petrylak*, New Haven, CT

Introduction

ARV-766 is a second-generation PROteolysis TArgeting Chimera (PROTAC) AR degrader that targets wild-type AR and clinically relevant mutants. Parts A & B of the first-in-human study (NCT05067140) are assessing ARV-766 monotherapy in men with metastatic castration-resistant prostate cancer (mCRPC; target n=150). In part A (dose escalation), patients (pts) who had =2 prior therapies (including =1 NHA) were given ARV-766 orally once daily (QD) in ascending doses to assess safety and tolerability and select recommended phase 2 doses (RP2Ds); in part B (cohort expansion), pts treated with 1–3 prior NHAs and =2 chemotherapy regimens were randomized to receive 100 mg or 300 mg ARV-766 orally QD to evaluate the antitumor activity of the RP2Ds. The NHA abiraterone is approved for pts with mCRPC or high-risk metastatic castration-sensitive prostate cancer (mCSPC). Combining drugs that target different steps of the AR signaling pathway may yield a synergistic treatment effect. Part C of this study will assess the addition of ARV-766 to abiraterone for the treatment of NHA-naïve mCRPC or mCSPC.

Methods

Part C will enroll =24 men (aged =18 y) with histologically, pathologically, or cytologically confirmed mCRPC or mCSPC, Eastern Cooperative Oncology Group performance status score of 0 or 1, and no prior NHA treatment. Pts will receive escalating doses of ARV-766 (starting at 100 mg QD) with standard-dose abiraterone to assess drug-drug interaction (DDI) and safety of the combination; pts will also receive androgen deprivation therapy of choice. Dose escalation will follow a conventional 3+3 cohort design based on safety and abiraterone pharmacokinetics. The primary endpoints of part C are first-cycle dose-limiting toxicities and frequency and severity of adverse events (AEs) and laboratory abnormalities.

Results

As of August 23, 2023, 84 pts with mCRPC received ARV-766 monotherapy in parts A & B. Treatment-related AEs (TRAEs) reported in =10% of these pts were fatigue (29%; 2% grade 3), nausea (14%; 0 grade 3), diarrhea (11%; 1% grade 3), vomiting (11%, 0 grade 3), decreased appetite (11%, 0 grade 3), and alopecia (10%). There were no grade =4 TRAEs with ARV-766 monotherapy; 3 pts had TRAEs leading to ARV-766 discontinuation.

Conclusions

ARV-766 monotherapy was well tolerated in NHA-exposed pts with mCRPC; analyses of anti-tumor activity in parts A & B are ongoing. Part C of the study will assess the safety, tolerability, and DDI of combination ARV-766/abiraterone treatment in NHA-naïve mCRPC or mCSPC.

Source Of Funding

This study is sponsored by Arvinas Androgen Receptor, Inc.