Study of ORIC-101 in Combination With Enzalutamide

Inclusion Criteria:

Histologically or cytologically confirmed adenocarcinoma of the prostate
Metastatic prostate cancer currently being treated with enzalutamide (Xtandi®) 160 mg once daily plus surgical or ongoing chemical castration, with baseline testosterone level <50 ng/dL
Must have been on treatment with enzalutamide for at least 3 months prior to documented evidence of PSA progression defined as per PCWG3: minimum of 2 rising values (3 measurements) obtained a minimum of one week apart with the latest result being at least 2.0 ng/mL (or 1.0 ng/mL if PSA rise is the only indication of progression)

Agreement and ability to undergo on-study core biopsies, as follows, through a procedure that is deemed to be clinically feasible and not carry significant risk:

one pre-treatment tumor biopsy obtained while on treatment with enzalutamide prior to enrollment on this study; and
one post-treatment tumor biopsy during Cycle 2
one end of treatment tumor biopsy (optional)
ECOG performance status 0 or 1
Life expectancy of at least 3 months

Adequate organ function as defined by the following criteria:

ANC ≥1500 cells/mm3 (1.5 × 103 cells/mm3)
Platelets ≥100,000 /µL (100 × 109 /L)
Hemoglobin ≥9.0 g/dL (90 g/L)
AST (SGOT) or ALT (SGPT) ≤2.5 × ULN, ≤5.0 × ULN for patients with liver metastases
Bilirubin ≤1.5 × ULN; patients with a known history of Gilbert's syndrome and/or isolated elevations of indirect bilirubin are eligible
QTcF ≤480 msec
Capable of giving signed informed consent

Exclusion Criteria:

No intervening therapy between enzalutamide treatment and enrollment on this study
Any other active malignancy, with the exception of adequately treated non-melanoma skin cancer, adequately treated superficial bladder cancer, stage 1 or 2 solid tumor malignancies without evidence of disease, or other solid tumors curatively treated with no evidence of disease for ≥5 years from enrollment
Current treatment on another therapeutic clinical trial
Prior or current treatment with ORIC-101 or any other GR antagonist (eg, CORT-125281, mifepristone, relacorilant)
Prior chemotherapy in the metastatic castration-resistant prostate cancer setting
Prior treatment with a second-generation AR modulator (eg, apalutamide, abiraterone, darolutamide)
History of Cushing's syndrome or adrenal insufficiency
History or presence of CNS metastases
History of seizures or condition that may predispose to seizures
Current (at C1D1) or requirement for chronic use of systemic corticosteroids with the exception of inhaled, topical, intraocular, intranasal, or intraarticular corticosteroids
Current (within 10 days prior to first dose of ORIC-101) or expected on-study treatment with specified strong CYP3A4 inhibitors or inducers
Receiving any other anticancer therapy, including radiotherapy within 21 days prior to C1D1. Patients must have recovered from all toxicities from prior anticancer therapies and/or radiotherapy
Major surgery within 21 days prior to C1D1 or incomplete recovery from adverse effects resulting from such procedure
Known human immunodeficiency virus (HIV) infection, unless patient is healthy and has a low risk of AIDS-related outcomes
Active Hepatitis B or C infection
Any other condition or circumstance (eg, clinical, psychological, familial, sociological, inability to swallow oral study drug) that, in the opinion of the investigator, may interfere with protocol compliance or contraindicates participation in the study