Phase I/II trial of enzalutamide (Enz) plus mifepristone (Mif) for metastatic castration-resistant prostate cancer (mCRPC).

Abstract

91 Background: Resistance to androgen receptor (AR) targeted therapies is common in mCRPC. Glucocorticoid receptor (GR) expression increases with AR inhibition in patients (pts) and blockade of GR signaling inhibits CRPC growth in preclinical models when combined with AR blockade. We thus conducted a phase I/II open label trial of Enz combined with Mif, a GR, AR, and progesterone receptor antagonist for pts with mCRPC to assess the feasibility and impact on disease progression with dual AR/GR antagonism. Methods: The phase I dose escalation portion assessed the safety of the two-drug combination and a recommended phase II dose (R2PD) was determined based on safety, pharmacokinetic and endocrine assessments. In the phase II portion, patients (pts) received 12 weeks of Enz (160mg/day) followed by randomization to Enz alone or Enz plus Mif with PSA-progression free survival (PFS) as the primary endpoint. 42 pts were to randomize to each arm to provide 80% power to detect a hazard ratio of 0.6, with a one-sided alpha of 0.1; there was a planned interim futility analysis after 50% of progression events. Results: 106 pts (18 phase I/88 phase II) were enrolled. Pts had a median age of 70 (range 53-89) and baseline PSA of 12.8 (range 0.1-755). 34% of pts received prior docetaxel. The RP2D was 120mg/day Enz and 300mg/day Mif. In phase II, 33 patients were randomized to each arm, with well-balanced baseline demographics. 22 pts were not randomized (15 due to disease progression, 2 due to toxicity, and 5 due to the interim study analysis). The interim analysis showed no difference between arms in PSA-PFS (hazard ratio = 1.34, p=0.395), 12-month PSA-PFS of 31% in both arms, and per-protocol, the trial was stopped. Toxicities were similar in the arms, e.g. fatigue (12% vs. 14%), hot flashes (6% vs. 5%), and pain (4% vs. 4%). Conclusions: The addition of Mif to Enz following a 12-week Enz lead-in did not delay time to PSA progression. Further analyses of secondary endpoints, including translational biomarkers such as hormone levels, GR/AR-v7 expression in circulating tumor cells and cell free DNA analyses are ongoing. Clinical trial information: NCT02012296.

Androgen Receptor Signaling in Prostate Cancer and Therapeutic Strategies

“…Loss of TLE3, a transcriptional corepressor, leads to increased GR expression and is implicated in apalutamide and enzalutamide resistance [131]. However, the phase I/II open-label trial of enzalutamide combined with mifepristone, a GR antagonist, in patients with mCRPC showed no benefit in delaying time to PSA-P compared to enzalutamide alone (HR = 1.34, p = 0.395) [135,136]. Another phase I/II trial that assessed a selective GR antagonist, CORT125281, plus enzalutamide in mCRPC patients whose cancer progressed on abiraterone is ongoing [137].…”

The Dual Androgen Receptor and Glucocorticoid Receptor Antagonist CB-03-10 as Potential Treatment for Tumors that have Acquired GR-mediated Resistance to AR Blockade

“…The combination of a GR antagonist and enzalutamide is currently being tested in two clinical trials (NCT03674814, NCT03437941). However, the initial result of a phase I/II trial with combined mifepristone and enzalutamide in metastatic CRPC yielded no clinical benefit based on time to PSA progression (21). A possible explanation is that mifepristone's GR agonist activity may have limited its efficacy in this trial.…”

Androgen Receptor Signaling in Prostate Cancer and Therapeutic Strategies

“…Loss of TLE3, a transcriptional corepressor, leads to increased GR expression and is implicated in apalutamide and enzalutamide resistance (124). However, the phase I/II open-label trial of enzalutamide combined with mifepristone, a GR antagonist, in patients with mCRPC showed no benefit in delaying time to PSA-P compared to enzalutamide alone (HR=1.34, p=0.395) (128,129). Another phase I/II trial that assessed a selective GR antagonist, CORT125281, plus enzalutamide in mCRPC patients whose cancer progressed on abiraterone is ongoing (130).…”