ORIC-101 + enzalutamide

ORIC-101 + enzalutamide is a **combination therapy** investigated for treating metastatic castration-resistant prostate cancer (mCRPC) that has progressed on enzalutamide. **ORIC-101** is a potent, selective, orally bioavailable small molecule antagonist of the **glucocorticoid receptor**, developed to overcome resistance mechanisms to androgen receptor inhibitors such as enzalutamide. **Enzalutamide** is a well-established androgen receptor inhibitor. The goal of the combination is to counteract glucocorticoid receptor–driven resistance that can emerge during enzalutamide therapy. Phase 1b clinical trials demonstrated the regimen was generally well tolerated at the recommended phase 2 dose (240 mg ORIC-101 and 160 mg enzalutamide once daily). However, efficacy endpoints (disease control rate, objective response rate, PSA response) did not meet prespecified thresholds, and the trial was terminated after interim analysis didn't show sufficient clinical benefit. Preliminary exploratory data hint at benefits in patients with high tumor glucocorticoid receptor expression, but these need further confirmation[1][2][3][5].