Phase I Study of ORIC-101, a Glucocorticoid Receptor Antagonist, in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer Progressing on Enzalutamide

Author:

Abida Wassim1ORCID,Hahn Andrew W.2ORCID,Shore Neal3ORCID,Agarwal Neeraj4ORCID,Sieber Paul5ORCID,Smith Matthew R.6ORCID,Dorff Tanya7ORCID,Monk Paul8ORCID,Rettig Matthew9ORCID,Patel Rupal10ORCID,Page Anne10ORCID,Duff Maureen10ORCID,Xu Rongda10ORCID,Wang Jian10ORCID,Barkund Shravani10ORCID,Pankov Aleksandr10ORCID,Wang Amber10ORCID,Junttila Melissa R.10ORCID,Multani Pratik S.10ORCID,Daemen Anneleen10ORCID,Chow Maneval Edna10ORCID,Logothetis Christopher J.2ORCID,Morris Michael J.1ORCID

Affiliation:

1. 1Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.

2. 2Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

3. 3CURC, Myrtle Beach, South Carolina.

4. 4Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.

5. 5Keystone Urology Specialists, Lancaster, Pennsylvania.

6. 6Massachusetts General Hospital, Boston, Massachusetts.

7. 7City of Hope, Duarte, California.

8. 8The Ohio State University, Arthur James Cancer Hospital, Columbus, Ohio.

9. 9VA Greater Los Angeles, Los Angeles, California.

10. 10ORIC Pharmaceuticals, South San Francisco, California.

Abstract

Abstract Purpose: Increased glucocorticoid receptor (GR) signaling is a proposed compensatory mechanism of resistance to androgen receptor (AR) inhibition in metastatic castration-resistant prostate cancer (mCRPC). ORIC-101 is a potent and selective orally-bioavailable GR antagonist. Patients and Methods: Safety, pharmacokinetic/pharmacodynamic, 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 once daily were tested in combination with enzalutamide 160 mg once daily. Pharmacokinetics/pharmacodynamics was assessed after a single dose and at steady state. Disease control rate (DCR) at 12 weeks was evaluated at the recommended phase 2 dose (RP2D). Results: 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 adverse events were fatigue (38.7%), nausea (29.0%), decreased appetite (19.4%), and constipation (12.9%). Pharmacokinetic/pharmacodynamic 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% confidence interval: 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 prostate cancer suggested possible benefit in patients with high GR expression and no other resistance markers, although this would require confirmation. Conclusions: 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.

Funder

National Cancer Institute

Publisher

American Association for Cancer Research (AACR)

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