Patients with metastatic prostate cancer

Must have undergone bilateral orchiectomy or be willing to continue GnRH analogue or antagonist to maintain castrate levels of testosterone

Prior therapies:

Part I (single agent ORIC-944 dose escalation): Any number of prior therapies are allowed, but must have progressed after at least one line of next generation ARPI (abiraterone, apalutamide, darolutamide, or enzalutamide) and must not have received more than 2 chemotherapy regimens in the mCRPC setting

Part II (ARPI combination dose escalation): Must have received only 1 prior line of ARPI (abiraterone, apalutamide, darolutamide, or enzalutamide) in any setting; may have also received up to 1 prior line of chemotherapy in the mCSPC setting

Part III (ARPI combination dose optimization): In addition to up to 1 prior line of chemotherapy in the mCSPC setting:

Cohorts A and B: received only one 1 prior line of abiraterone in any setting

Cohorts C and D: received only one 1 prior line of apalutamide, darolutamide, or enzalutamide in any setting: * Evidence of progressive disease by PCWG3 criteria for study entry * rising PSA, defined as a minimum of 2 rising values 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), or * confirmation of 2 new bone lesions on last systemic therapy, or * soft tissue progression per RECIST 1.1 * Measurable and/or evaluable disease by RECIST 1.1 * Agreement and ability to undergo on-study punch skin biopsies and core tumor biopsies * ECOG performance status of 0 or 1 * Adequate organ function

Minimum age: 18

History or presence of CNS metastases, unless previously treated and stable

History of class III or IV congestive heart failure or severe non-ischemic cardiomyopathy, unstable or poorly controlled angina, myocardial infarction, or ventricular arrhythmia within the previous 6 months

Known, symptomatic human immunodeficiency virus (HIV) infection

Active symptomatic Hepatitis B or C infection; patients with well controlled disease are eligible

Active gastrointestinal disease (eg, Crohn's disease, ulcerative colitis, short gut syndrome, etc) or other malabsorption syndromes that would reasonably impact drug absorption per investigator judgement

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