Increased GR signaling is a proposed compensatory mechanism of resistance to AR inhibition in mCRPC. ORIC-101 is a potent and selective orally-bioavailable GR antagonist.
Safety, PK/PD, and antitumor activity of ORIC-101 in combination with enzalutamide were studied in patients with mCRPC progressing on enzalutamide. ORIC-101 doses ranging from 80 to 240 mg QD were tested in combination with enzalutamide 160 mg QD. PK/PD was assessed after a single dose and at steady-state. Disease control rate at 12 weeks (DCR) was evaluated at the RP2D.
A total of 41 patients were enrolled. There were no dose limiting toxicities and the RP2D was selected as 240 mg of ORIC-101 and 160 mg of enzalutamide daily. At the RP2D, the most common treatment-related AEs were fatigue (38.7%), nausea (29.0%), decreased appetite (19.4%), and constipation (12.9%). PK/PD data confirmed ORIC‑101 achieved exposures necessary for GR target engagement. Overall, for 31 patients treated at the RP2D, there was insufficient clinical benefit based on DCR (25.8%; 80% CI: 15.65%, 38.52%) which did not meet the prespecified target rate, leading to termination of the study. Exploratory subgroup analyses based on baseline GR expression, presence of AR resistance variants, and molecular features of aggressive variant PC suggested possible benefit in patients with high GR expression and no other resistance markers, although this would require confirmation.
Although the combination of ORIC-101 and enzalutamide demonstrated an acceptable tolerability profile, GR target inhibition with ORIC-101 did not produce clinical benefit in men with metastatic prostate cancer resistant to enzalutamide.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2024 Jan 16 [Epub ahead of print]
Wassim Abida, Andrew W Hahn, Neal Shore, Neeraj Agarwal, Paul Sieber, Matthew R Smith, Tanya Dorff, J Paul Monk, Matthew B Rettig, Rupal Patel, Anne Page, Maureen Duff, Rongda Xu, Jian Wang, Shravani Barkund, Aleksandr Pankov, Amber Wang, Melissa Junttila, Pratik S Multani, Anneleen Daemen, Edna Chow Maneval, Christopher J Logothetis, Michael J Morris
Memorial Sloan Kettering Cancer Center, New York, NY, United States., The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Carolina Urologic Research Center, Myrtle Beach, SC, United States., Huntsman Cancer Institute, Salt lake City, UT, United States., Keystone Urology Specialists, Lancaster, PA, United States., Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, United States., City Of Hope National Medical Center, Duarte, CA, United States., The Ohio State University and The James Comprehensive Cancer Center, Columbus, OH, United States., University of California, Los Angeles, Los Angeles, CA, United States., ORIC Pharmaceuticals, South San Francisco, CA, United States., ORIC Pharmaceuticals, San Diego, California, United States., Memorial Sloan Kettering Cancer Center, New York, New York, United States.