Study of ORIC-101 in Combination With Enzalutamide

The purpose of this study is to establish the recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of ORIC-101 in combination with enzalutamide (Xtandi®) when administered to patients with metastatic prostate cancer progressing on enzalutamide.

ORIC-101 is a small molecule GR antagonist being developed for the treatment of patients with solid tumor malignancies. Mechanistically, ORIC-101 inhibits GR transcriptional activity and blocks the pro-survival signals mediated by the activated nuclear receptor.

This is an open-label, single arm, multicenter, dose escalation followed by dose expansion study to assess the safety and preliminary antitumor activity of ORIC-101 in combination with enzalutamide in patients progressing on enzalutamide. Patients deemed eligible will receive treatment with ORIC-101 in addition to continuing their current enzalutamide therapy.

Escalating dose levels of ORIC-101 will be administered orally, once daily in combination with enzalutamide 160 mg. Parallel enrollment for assessment of PK/PD modulation in up to 3 additional patients presenting with tumors expressing high levels of GR (GR-high) may be performed at each dose level after the dose level has cleared the initial dose-limiting toxicity evaluation period; these additional patients may serve as supplemental patients for selection of the maximum tolerated dose and/or RP2D.

Dose expansion will further evaluate the safety and preliminary antitumor activity of ORIC-101 in patients presenting with different levels of GR expressing-tumors.

Eligibility Criteria:
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