Purpose: Majority of patients with metastatic prostate cancer who receive androgen deprivation therapy and androgen receptor (AR) signaling inhibitors progress. Activation of the glucocorticoid receptor (GR) is associated with ARSI-resistance. This single-arm phase I trial assessed safety and pharmacokinetic feasibility of combined AR antagonist (enzalutamide) and selective GR modulator (relacorilant) in metastatic castration-resistant prostate cancer (mCRPC) patients.
Patients and methods: This was a phase I trial (NCT03674814) of relacorilant and enzalutamide in refractory mCRPC patients enrolled using 6+3 design. Enzalutamide dose was kept constant at 120 mg/day with escalating doses of relacorilant based on safety and pharmacokinetic measures in cohorts of ≥ 6 patients. Primary objective was safety and establishment of pharmacologically active doses. Secondary objectives were related to antitumor activity.
Results: Thirty-five mCRPC patients were enrolled. Twenty-three were accrued across 3 dose cohorts in the dose escalation phase and twelve enrolled at the recommended phase 2 dose. The combination was generally well-tolerated and safe and achieved desirable enzalutamide pharmacokinetics. RP2D of 120 mg/day + 150 mg/day respectively was established. Median time on study was 2.2 months with 4 patients remaining on study for longer than 11 months. Four of twelve evaluable patients had a PSA partial response.
Conclusions: This is the first prospective trial combining an AR antagonist and a non-steroidal selective GR modulator. The combination was safe and well tolerated with PSA response and prolonged disease control observed in a limited subset of patients. Further prospective trials are justified to evaluate efficacy and identify predictive biomarkers of response.