BMX inhibition and HSD3B1-driven resistance in prostate cancer in the Maverick trial.

• DOI: 10.1200/jco.2023.41.6_suppl.144
• Publication Date: 2023-03-14T15:22:32Z
• Authors: Nima Sharifi; Rana R. McKay; Jake Vinson; Mike A. Royal; Joshua Michael Lang; Eric A. Klein; Xiuxiu Li; Michael Berk; Christopher Goins; Mohammad Alyamani; Yoon-Mi Chung; Chenyao Wang; Mona Patel; Nityam Rathi; Ziqi Zhu; Belinda Willard; Shaun Stauffer
• Keywords: Enzalutamide

144 Background: Kinase inhibitors have been ineffective in prostate cancer and no known role androgen biosynthesis. Inheritance of the adrenal-permissive HSD3B1(1245C) allele encodes a 3βHSD1 enzyme missense that up-regulates rate-limiting step biosynthesis from non-gonadal precursor steroids confers poor clinical outcomes castration-resistant (CRPC). About half all men with inherit HSD3B1 allele. Multiple studies demonstrate inheritance more rapid progression on ADT others also suggest worse CRPC even after treatment abiraterone or enzalutamide. However, there is method to clinically block 3βHSD1. Furthermore, not be phosphorylated. Methods: Mass spectrometry was used identify protein phosphorylation sites steroid metabolites, genetic pharmacologic methods were kinase required for mouse xenograft performed BMX inhibition. The identified mechanism design launch multicenter phase 2 study inhibitor abivertinib combination metastatic CRPC. Results: activity requires tyrosine at Y344 by kinase. Androgen blocked phosphorylation-defective 344F, knockdown, inhibition using zanubrutinib suppresses growth C4-2 VCaP models blocking intratumoral synthesis tumor receptor (AR) signaling. Discovery this provides rationale Maverick trial abivertinib, inhibitor, combined abiraterone, (NCT05361915). Eligibility includes 1) presence CRPC, 2) measurable and/or non-measurable disease, 3) confirmed positivity via central testing (cap heterozygosity 50%). Patients will enrolled arms: naïve (n=45) progressing (n=55). All patients receive 200mg twice daily 1000mg prednisone 5mg mouth daily. primary outcome 6-month radiographic progression-free survival. On-treatment biopsies inform mechanisms response resistance patients. Conclusions: phosphorylation, test proof-of-concept inheritance. Clinical information: NCT05361915 .