Background: Preclinical studies have shown that activation of the glucocorticoid receptor (GR) leads to resistance to antiandrogens, which is reversed by GR inhibition. ORIC-101 is a potent, selective, orally bioavailable small molecule GR antagonist undergoing clinical development in combination with enzalutamide in patients with metastatic prostate cancer (NCT04033328). Methods: Ten patients were enrolled in the dose escalation portion of the Phase 1b study during which three dose levels of ORIC-101 given once daily were evaluated in combination with 160 mg enzalutamide. Translational markers were measured both pre-treatment and on study, including PD biomarkers, blood cortisol, GR and AR protein levels, and genomic alterations. PD biomarkers FKBP5, GILZ and PER1 were assessed by RT-qPCR in peripheral blood mononuclear cells (PBMCs), collected on multiple days and times in the first two cycles before and after dosing. PD modulation and target coverage were evaluable in 9 out of 10 patients. In tumor biopsies with >50 tumor cells, GR, AR and PTEN protein status were evaluated by immunohistochemistry (IHC). Liquid biopsies were collected before treatment, at the end of Cycle 2, and/or the end of treatment: nuclear GR and ARv7 protein levels were measured on circulating tumor cells (CTCs) by immunofluorescence (Epic Sciences, San Diego, CA), mutations and copy number alterations in cancer genes were captured in plasma with the 500-gene GuardantOMNI® ctDNA assay (Redwood City, CA). Results: PD suppression after one dose of ORIC-101 was observed in PBMCs of all patients. ORIC-101 reached steady-state target engagement within the first cycle in 6 out of 9 evaluable patients across dose levels, including at the RP2D. Nuclear GR protein was detected by IHC in the 6 pre-treatment biopsies, with H-scores ranging from 11 to 298 (median 95, IQR 55-148). Reduction of GR protein was observed in 3 out of 4 matched on study biopsies (pre-treatment H-scores 110-298), indicating potential elimination of GR positive tumor cells, while the fourth patient had low baseline GR levels (H-score 11). Pre-treatment AR protein levels were consistently high (IHC H-scores 230-300). AR alterations observed in ctDNA or CTCs were L702H (n=1 patient), H875Y (n=1), amplification (n=2), and ARv7 (n=2). PTEN protein aberrations were identified in two patients. The amount of tumor shedding in this cohort ranged from 0.24 to 82% (median 2.2%, IQR 0.54-12.1%), comparable to a clinical cohort of ~10,000 prostate tumors profiled with Guardant360® (Guardant Health). Prevalent genomic alterations at time of enrollment included TP53, RB1, BRCA2, ATM and SPOP, with minimal new genomic changes occurring on treatment. Conclusions: Biomarker data from patients enrolled in the Phase 1b study provide evidence of PD modulation, steady-state target coverage, and on-target tumor cell eradication at all dose levels. Tumor characterization in association with clinical outcome provides an opportunity to refine the patient population during the ongoing dose expansion portion of the study.

Citation Format: Anneleen Daemen, Shravani Barkund, Ann Johnson, Aleksandr Pankov, Amber W. Wang, Haiying Zhou, Pratik S. Multani, Edna Chow Maneval, Lori S. Friedman, Rupal Patel. Biomarker results supporting selection of RP2D from a phase 1b study of ORIC-101, a glucocorticoid receptor antagonist, in combination with enzalutamide in patients with metastatic prostate cancer progressing on enzalutamide [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P015.