A phase I trial of enzalutamide plus selective glucocorticoid receptor modulator relacorilant in patients with metastatic castration resistant prostate cancer.

Abstract

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. 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. 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. 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.