Abstract P041: Initial results from a phase 1b study of ORIC-101, a glucocorticoid receptor antagonist, in combination with enzalutamide in patients with metastatic prostate cancer
Authors: Abida Wassim , Agarwal Neeraj , Hahn Andrew W. , Shore Neal , Sieber Paul , Dorff Tanya , Rettig Mathew , Smith Mathew , Monk Paul , Xu Rongda , Johnson Ann , Daemen Anneleen , Maneval Edna Chow , Multani Pratik S. , Patel Rupal , Morris Michael J. 
Published: December 2021

Abstract
Background: Upregulation of the glucocorticoid receptor (GR) is a potential mechanism of resistance to enzalutamide and other androgen receptor (AR) modulators in prostate cancer. Preclinical studies have demonstrated that GR activation can bypass enzalutamide-mediated AR inhibition and support prostate cancer cell growth. Overexpression of GR is associated with poor outcomes in castration-resistant prostate cancer patients (CRPC) treated with enzalutamide. ORIC-101 is a potent and selective orally bioavailable, small molecule antagonist of GR. Mechanistically, ORIC-101 inhibits GR transcriptional activity and blocks the pro-survival signals mediated by the activated nuclear hormone receptor. Methods: A modified interval 3+3 (i3+3) design was used to assess safety, pharmacokinetics (PK), and pharmacodynamics (PD) to select the Recommended Phase 2 Dose (RP2D) of ORIC-101 in combination with enzalutamide in patients with metastatic CRPC progressing on enzalutamide 160 mg, dosed once daily (NCT04033328). ORIC-101, at doses ranging from 80 to 240 mg once daily, given in a continuous dosing regimen, was added to enzalutamide at the time of disease progression. Plasma PK and PD biomarkers were assessed on multiple days and times before and after dosing. PD modulation in blood-derived peripheral blood mononuclear cells (PBMCs) was assessed by RT-qPCR for GR target genes. Antitumor activity was assessed by Prostate Cancer Clinical Trials Working Group 3 (PCWG3) and RECIST 1.1. Results: 10 patients were treated in 3 cohorts in the dose escalation portion of the study. ORIC-101 exposure increased with dose and no drug-drug interaction (DDI) was observed that necessitated reduction from the standard enzalutamide dose of 160 mg. No dose limiting toxicities were observed at any dose level. Based upon plasma exposure and PD modulation, the RP2D was established as 240 mg ORIC-101 plus 160 mg enzalutamide, both dosed once daily continuously in 28-day cycles. All adverse events (AEs) were Grade 1 or 2 with the most common (&gt;15%), treatment-related AEs being fatigue (40%), nausea (30%), constipation (20%), decreased appetite (20%), high aspartate aminotransferase (20%), high alkaline phosphatase (20%), and headache (20%). There were no Grade ≥3 treatment-related AEs. Biomarker data demonstrated ORIC-101 induced reduction in GR target gene expression in PBMCs, indicating PD modulation across dose levels of ORIC-101. Data will be updated at the time of the presentation. Conclusions: Preliminary evidence suggests that ORIC-101 effectively modulates GR and has an acceptable tolerability profile when combined with enzalutamide. Dose expansion is ongoing at the RP2D.
Citation Format: Wassim Abida, Neeraj Agarwal, Andrew W. Hahn, Neal Shore, Paul Sieber, Tanya Dorff, Mathew Rettig, Mathew Smith, Paul Monk, Rongda Xu, Ann Johnson, Anneleen Daemen, Edna Chow Maneval, Pratik S. Multani, Rupal Patel, Michael J. Morris. Initial results from a phase 1b study of ORIC-101, a glucocorticoid receptor antagonist, in combination with enzalutamide in patients with metastatic prostate cancer [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 P041.