1803P - Phase I/II study of bavdegalutamide, a PROTAC androgen receptor (AR) degrader in metastatic castration-resistant prostate cancer (mCRPC): Radiographic progression-free survival (rPFS) in patients (pts) with <italic>AR</italic> ligand-binding domain (LBD) mutations

Background

Pts with mCRPC and mutations in AR LBD (amino acids 671-920) have poor prognosis. The oral PROteolysis TArgeting Chimera (PROTAC) AR degrader bavdegalutamide (bavdeg; ARV-110) showed clinical activity in previously treated pts with mCRPC in a phase 1/2 study (NCT03888612), with enhanced activity seen in pts with the AR LBD mutations T878 and/or H875.

Methods

In phase 1, pts with mCRPC and ≥2 prior therapies (including a novel hormonal agent [NHA]) received bavdeg 35–700 mg once daily (QD) or 210–420 mg twice daily. In phase 2, pts with mCRPC and 1–2 prior NHAs ± prior chemotherapy were assigned to biomarker-defined subgroups; pts who had 1 prior NHA and no prior chemotherapy were enrolled in a clinically defined subgroup. All phase 2 pts received 420 mg bavdeg QD. In exploratory analyses across the phase 1/2 population treated with 420 mg bavdeg QD, efficacy was assessed in pts with AR 878/875 mutation(s) without an AR L702 mutation (AR 878/875 pts) and in those with any AR LBD missense mutation except AR L702H alone (AR LBD pts).

Results

As of Dec 20, 2022, median rPFS (95% CI) per PCWG3 was 11.1 months (7.10–not reached) in 25 AR 878/875 pts (10 events; 4 pts still on treatment) and 8.1 months (3.81–10.97) in 44 AR LBD pts (20 events; 5 pts still on treatment). Best prostate-specific antigen (PSA) declines of ≥50% after ≥1 month of PSA follow-up were seen in 56.0% of AR 878/875 pts (n=25) and 37.2% of AR LBD pts (n=43). In response-evaluable pts with measurable disease at baseline, overall response rate was 9.1% in AR 878/875 pts (n=11) and 10.0% in AR LBD (n=20) pts; 55% and 50%, respectively, had stable disease. There were no grade ≥4 treatment-related adverse events (TRAEs) with 420 mg bavdeg (n=158 across phase 1/2); any grade TRAEs reported in ≥20% of pts were nausea (54%; 1% grade 3), fatigue (35%; 1% grade 3), vomiting (31%; 1% grade 3), diarrhea (25%; 2% grade 3) and decreased appetite (23%; 0 grade 3).

Conclusions

Bavdeg had encouraging efficacy in post-NHA pts with mCRPC and AR 878/875 or any AR missense LBD mutation (excluding AR L702H alone) and was tolerable; these pt populations will be analyzed in a phase 3 study of bavdeg.

Clinical trial identification

NCT03888612.

Editorial acknowledgement

Legal entity responsible for the study

Arvinas Operations, Inc.

Funding

Arvinas Androgen Receptor, Inc.

Disclosure

D.P. Petrylak: Financial Interests, Personal, Other, Consultant Fees: Ada Cap (Advanced Accelerator Applications), Amgen, Astellas, AstraZeneca, Bayer, Bicycle Therapeutics, Boehringer Ingelheim, BMS, Clovis Oncology, Eli Lilly, Exelixis, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Ipsen, Janssen, Merck & Company Inc, Mirati, Monopteros, Pfizer, Pharmacyclics, Regeneron, Roche, Sanofi Aventis Pharmaceuticals, Seattle Genetics, Urogen; Financial Interests, Personal, Stocks/Shares: Bellicum (Sold 7/2020), Tyme (sold 10/2019); Financial Interests, Institutional, Invited Speaker: Ada Cap (Advanced Accelerator Applications), Agensys Inc, Arvinas, Astellas, AstraZeneca, Bayer, BioXcel Therapeutics, BMS, Clovis Oncology, Daiichi Sankyo Company Limited, Eisai, Eli Lilly, Endocyte, Ferring, Genentech, Gilead Sciences, Innocrin, MedImmune, Medivation, Merck, Mirati, Novartis, Pfizer, Progenics, Replimune, Roche, Sanofi Aventis, Seattle Genetics. B. Garmezy: Financial Interests, Institutional, Research Grant: AbbVie, AstraZeneca, CRISPR Therapeutics, Exelixis, Genentech, Janssen, Loxo Oncology, Arcus Biosciences, Xencor, AVEO Oncology, Zenshire, Accutar Biotechnology, Kinnate Biopharma, Jubilant Therapeutics, Janux Therapeutics, Mink Therapeutics, Nuvation Bio, Profound Bio, Kineta; Financial Interests, Institutional, Other, Consulting: Amgen, Arvinas, Aveo, Bayer, Exelixis, Janssen, Merck, Sanofi-Aventis. J. Shen: Financial Interests, Personal, Advisory Board: Bayer, Kite/Gilead, Sanofi, AstraZeneca; Financial Interests, Local PI: Ambrx, Arvinas, BMS, MacroGenics, Merck, Eli Lilly, Exelixis. A. Rezazadeh Kalebasty: Financial Interests, Personal, Stocks/Shares: ECOM Medical; Financial Interests, Personal, Advisory Role: Exelixis, AstraZeneca, Bayer, Pfizer, Novartis, Genentech, BMS, EMD Serono, Immunomedics, Gilead Sciences; Financial Interests, Personal, Speaker’s Bureau: Janssen, Astellas Medivation, Pfizer, Novartis, Sanofi, Genentech/Roche, Eisai, AstraZeneca, BMS, Amgen, Exelixis, EMD Serono, Merck, Seattle Genetics/Astellas, Myovant Sciences, Gilead Sciences, AVEO; Financial Interests, Institutional, Funding: Genentech, Exelixis, Janssen, AstraZeneca, Bayer, BMS, Eisai, Macrogenics, Astellas Pharma, BeyondSpring Pharmaceuticals, BioClin Therapeutics, Clovis Oncology, Bavarian Nordic, Seattle Genetics, Immunomedics, Epizyme, Novartis, Arvinas, Amgen, POINT Biopharma, Merck, Mirati Therapeutics; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Genentech, Prometheus, Astellas Medivation, Janssen, Eisai, Bayer, Pfizer, Novartis, Exelixis, AstraZeneca. O. Sartor: Financial Interests, Personal, Stocks or ownership: AbbVie, Cardinal Health, Clarity Pharmaceuticals, Convergent, Eli Lilly, Fusion Pharmaceuticals, Point Biopharma, Ratio, Telix, United Health Group; Financial Interests, Personal, Advisory Role: Advanced Accelerator Applications, Amgen, ART BioScience, Astellas Pharma, AstraZeneca, Bayer, Clarity Pharmaceuticals, EMD Serono, Fusion Pharmaceuticals, Isotopen Technologien, Janssen, MacroGenics, Novartis, Pfizer, Point Biopharma, Ratio, Sanofi, Telix Pharmaceuticals, TeneoBio; Financial Interests, Institutional, Research Funding: Advanced Accelerator Applications, Amgen, AstraZeneca, Bayer, InVitae, Janssen, Lantheus, Merck, Sanofi; Financial Interests, Personal, Licencing Fees or royalty for IP: patents for Saposin C and receptors as targets for treatment of benign and malignant disorders (U.S. patent awarded January 23, 2007; patent no. 7,166,691); Financial Interests, Personal, Expert Testimony: Sanofi; Financial Interests, Personal, Other, Reimbursement for travel, accommodations, or expenses: AstraZeneca, Bayer, Lantheus, Sanofi. R. Dreicer: Financial Interests, Personal, Advisory Board: Pfizer, Eisai, Propella, Merck, Astellas, Janssen, Giliead, Sanofi Genzyme; Financial Interests, Personal, Other, DSMB: aveo; Financial Interests, Institutional, Funding: Exilexis, Novartis. N. Agarwal: Financial Interests, Personal, Advisory Board, In the last two calendar years, I participated in the scientific advisory board of these pharma companies between February 2021 to April 2021. None after that: Merck, Aveo, Gilead, Lilly, Exelixis, Foundation Medicine; Financial Interests, Invited Speaker, I am involved in the following phase 3 trials as the trial co-chair: TALAPRO-2, TALAPRO-3 (both Pfizer), and CONTACT-2 (Exelxis): Pfizer, Exelixis; Financial Interests, Institutional, Other, I serve in the leadership of my cancer center (Huntsman Cancer Institute, University of Utah. Salt Lake City, UT, USA). There are multiple research projects sponsored by these companies which pay money to my institution: Arnivas, Astellas, AstraZeneca, Bavarian Nordic, Bayer, BMS, Calithera, Celldex, Crispr, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, GSK, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon.; Financial Interests, Invited Speaker, I am involved in the steering committee of the trials sponsored by these pharmas with no personal honorarium: AstraZeneca, Calithera, Clovis, Crispr, Eisai, Eli Lilly, Exelixis, Immunomedics, Janssen; Financial Interests, Invited Speaker, I am involved in the steering committee of the trials sponsored by these pharma companies with no personal honorarium: Merck, Nektar, New Link Genetics, Oric, Pfizer, Prometheus, Rexahn, Takeda, and Tracon. M. Hussain: Financial Interests, Personal, Other, Honoraria: UroToday, Merck, Astellas Pharma, AstraZeneca, Precisa, Medscape Zero, Targeted Oncology, AstraZeneca, Great Debates and Updates in GU Oncology, Clinical Care Options LLC; Financial Interests, Personal, Advisory Role: Pfizer, Novartis, Merck, Janssen, Tempus, Bayer, AstraZeneca, GSK, Convergent Therapeutics; Financial Interests, Institutional, Funding: Genentech, Pfizer, PCCTC, AstraZeneca, Bayer, Arvinas; Financial Interests, Personal, Other, Patent: SYSTEMS AND METHODS FOR TISSUE IMAGING, 3676 Our File: Serial Number: UM14437/US-1/PRO 60/923,385 UM-14437/US-2/ORD 12/101,753 US 8,185,186 (US patent number) Systems and methods for tissue imaging (issued patent) EP 08745653.9 (EP application number) Sy, METHOD OF TREATING CANCER Docket No: Serial Number: 224990/10-016P2/311733 61/481/671 Application Filed on: 5/2/2011, Dual Inhibition of MET and VEGF for the treatment of castration resistant prostate cancer and osteoblastic bone metastases. Applicant/Proprietor Exelexis, Inc. Application No/Patent No. 11764665.4- 1464 Application No/Patent No. 11764656.2-1464 Applicatio. E. Heath: Financial Interests, Personal, Other, Honoraria: Bayer, Sanofi, AstraZeneca, Genzyme, Janssen, Astellas Pharma, Caris Life Sciences, Johnson & Johnson/Janssen, Seattle Genetics; Financial Interests, Personal, Advisory Role: Bayer, Sanofi, AstraZeneca, Astellas Pharma, BMS, Janssen, Seattle Genetics; Financial Interests, Personal, Speaker’s Bureau: Sanofi; Financial Interests, Institutional, Research Funding: Tokai Pharmaceuticals, Seattle Genetics, Agensys, Dendreon, Genentech/Roche, Millennium, Celldex, Inovio Pharmaceuticals, Celgene, Zenith Epigenetics, Merck, AstraZeneca, Esanik, Oncolys BioPharma, Curemeta, BMS, eFFECTOR Therapeutics, Fortis, Astellas Pharma, Medivation, Ignyta, Synta, Caris Life Sciences, Boehringer Ingelheim, GSK, Merck Sharp & Dohme, Plexxikon, Corcept Therapeutics, Infinity Pharmaceuticals, Bayer, Modra Pharmaceuticals, Pellficure, Champions Oncology, AIQ Solutions, Novartis, Janssen Research & Development, Mirati Therapeutics, Peloton Therapeutics, Daiichi Sankyo Inc, Calibr, Eisai, Pharmacyclics, Five Prime Therapeutics, Arvinas, BioXCel Therapeutics, Calithera Biosciences, Corvus Pharmaceuticals, Exelixis, Gilead Sciences, Harpoon therapeutics, Roche, ITeos Therapeutics, Pfizer, POINT Biopharma; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Caris Life Sciences; Financial Interests, Personal, Other: Caris Centers of Excellence. R. Gedrich: Financial Interests, Personal, Full or part-time Employment: Arvinas; Financial Interests, Personal, Stocks/Shares: Arvinas. T. Yu: Financial Interests, Institutional, Full or part-time Employment: Arvinas, Inc.. D. Healey: Financial Interests, Personal, Full or part-time Employment: Arvinas; Financial Interests, Personal, Stocks/Shares: Pfizer, BMS, BioXcel Therapeutics. J. Parameswaran: Financial Interests, Personal, Full or part-time Employment: Arvinas. C.N. Sternberg: Financial Interests, Personal, Advisory Board, AD board and speaker at ESMO: Pfizer; Financial Interests, Personal, Advisory Board: MSD, AstraZeneca, Astellas, Sanofi-Genzyme, Roche-Genentech, Foundation Medicine, Immunomedics, Janssen; Financial Interests, Personal, Invited Speaker: Merck; Financial Interests, Personal, Advisory Board, Was the head if the oversight committee, of Phase III trial but last meeting over 1 year ago: Seattle Genetics; Financial Interests, Personal, Other, AD board: BMS; Financial Interests, Personal, Other, Speaker, owned by Prostate Cancer Foundation: Uro Today; Financial Interests, Personal, Other, Speaker, CME activities: Medscape. X. Gao: Financial Interests, Personal, Advisory Board: Bayer, Guardant Health, Flare Therapeutics, Silverback Therapeutics, PureTech Health, Myovant Sciences, PathAI; Financial Interests, Institutional, Principal Investigator: Arvinas, Exelixis, Pfizer, Harpoon Therapeutics, Aprea Therapeutics, Aravive, Merck, Poseida Therapeutics, TopAlliance Biosciences, Novartis, Regeneron, Bayer, ALX Oncology; Non-Financial Interests, Institutional, Principal Investigator: Arvinas, Exelixis, Pfizer, Harpoon Therapeutics, Aprea Therapeutics, Aravive, Merck, Poseida Therapeutics, TopAlliance Biosciences, Novartis, Regeneron, Bayer, ALX Oncology. All other authors have declared no conflicts of interest.