Phase I/II Trial of Enzalutamide and Mifepristone, a Glucocorticoid Receptor Antagonist, for Metastatic Castration-Resistant Prostate Cancer

Abstract

Purpose: Although androgen deprivation therapy (ADT) and androgen receptor (AR) signaling inhibitors are effective in metastatic prostate cancer, resistance occurs in most patients. This phase I/II trial assessed the safety, pharmacokinetic impact, and efficacy of the glucocorticoid receptor (GR) antagonist mifepristone in combination with enzalutamide for castration-resistant prostate cancer (CRPC).

Patients and methods: One hundred and six patients with CRPC were accrued. Phase I subjects were treated with enzalutamide monotherapy at 160 mg per day for 28 days to allow steady-state accumulation. Patients then entered the dose escalation combination portion of the study. In phase II, patients were randomized 1:1 to either receive enzalutamide alone or enzalutamide plus mifepristone. The primary endpoint was PSA progression-free survival (PFS), with radiographic PFS, and PSA response rate (RR) as key secondary endpoints. Circulating tumor cells were collected before randomization for exploratory translational biomarker studies.

Results: We determined a 25% dose reduction in enzalutamide, when added to mifepristone, resulted in equivalent drug levels compared with full-dose enzalutamide and was well tolerated. However, the addition of mifepristone to enzalutamide following a 12-week enzalutamide lead-in did not delay time to PSA, radiographic or clinical PFS. The trial was terminated early due to futility.

Conclusions: This is the first prospective trial of dual AR-GR antagonism in CRPC. Enzalutamide combined with mifepristone was safe and well tolerated but did not meet its primary endpoint. The development of more specific GR antagonists combined with AR antagonists, potentially studied in an earlier disease state, should be explored.

Trial registration: ClinicalTrials.gov NCT03674814 NCT03437941.

Conflict of interest statement

Conflict of Interest Statements (Disclosures):

Anthony V. Serritella

No disclosures

Daniel Shevrin

No disclosures

Elisabeth I. Heath

Honoraria - Bayer; Dendreon; Sanofi

Consulting or Advisory Role - Agensys

Speakers' Bureau - Sanofi

Research Funding - Agensys (Inst); Celgene (Inst); Celldex (Inst); Dendreon (Inst); Genentech/Roche (Inst); Inovio Pharmaceuticals (Inst); Millennium (Inst); Seattle Genetics (Inst); Tokai Pharmaceuticals (Inst)

James L. Wade

No disclosures

Elia Martinez

No disclosures

Amanda Anderson, Joseph Schonhoft, Lincy Chu

Employees of Epic Sciences and received Epic stock options at the time of their work

Theodore Karrison

No disclosures

Walter M. Stadler

Consultant (DSMB) - AstraZeneca, Bayer, Eisai, Merck, Pfizer, Treadwell Therapeutics

Consultant (Other) - Caremark/CVS, EMA Wellness

CME providers Speakers Bureau (sponsorship unknown): Applied Clinical Education, Dava Oncology, Global Academy for Medical Education, OncLive, PeerView, Research to Practice, Vindico

Grant/Research Support (to institution) - Abbvie, Amgen, Astra-Zeneca, Astellas (Medivation), Bayer, Bristol-Myers-Squibb, Boehringer-Ingelheim, Calithera, Clovis, Corvus, Eisai, Exilixis, Genentech (Roche), Johnson & Johnson (Janssen), Merck, Novartis, Pfizer, Seattle Genetics, Tesaro, X4Pharmaceuticals

Expert Witness - Apotex, DRL, Mylan, Sandoz

Miscellaneous/Editorial- Cancer (ACS), Up-To-Date

Russell Z. Szmulewitz

Honoraria - Astellas Pharma

Consulting or Advisory Role - Abbvie; Amgen; Astellas Pharma; AstraZeneca; Exelixis; Janssen Oncology; Merck; Pfizer; Sanofi

Research Funding - Abbvie; Astellas Pharma; Incyte; Janssen Oncology; Macrogenics

Patents, Royalties, Other Intellectual Property - Patent licensed by University of Chicago of which I am co-inventor to Corcept Therapeutics for combination AR/GR inhibition in prostate cancer

Travel, Accommodations, Expenses - Corcept Therapeutics

©2022 American Association for Cancer Research.

Figures

Figure 1:. Consort Diagram

Enz, enzalutamide; Enz alone, Enz 160mg daily after 12-week enzalutamide monotherapy lead in; Enz+Mif, Enz 120mg and Mif 300 mg daily after 12-week Enz lead-in; LFTs, liver function tests; Mif, mifepristone.

Figure 2:. Enzalutamide steady-state drug levels

Boxplot showing median, interquartile range, and full range of day 57/29 Enz and metabolite drug levels by dose escalation cohort. The Enz drug level trough drug concentration (Ctrough) achieved equivalent PK levels at a dosing of Enz 120 mg, Mif 300 mg with ratio of 1.0 for cohort 3, which became the recommended phase 2 dose. “X” denotes mean within each group. Abbreviations: Ctrough, concentration of Enz and metabolite on given day; Enz, enzalutamide; Mif, mifepristone.

Figure 3:. PSA and radiographic progression free survival

A. Kaplan-Meier plot of time to PSA progression while receiving Enz alone compared with Enz+Mif after combination dosing began at 12 weeks, showing a median progression-free survival hazard ratio of 1.09 comparing both arms (log rank p=0.83). B. Kaplan-Meier plot of time to radiographic progression. After a 12-week Enz lead-in, patients were randomized to receive either Enz alone or Enz+Mif, showing a median progression-free survival of NR in Enz alone arm and 16.5m in Enz+Mif arm (p=0.22). Abbreviations: Enz, Enzalutamide; Enz alone, Enz 160mg daily after 12-week enzalutamide monotherapy lead in; Enz+Mif, Enz 120mg and Mif 300 mg daily after 12 week Enz lead-in; Mif, Mifepristone; PSA, prostate specific antigen

Figure 4:. Effect of treatment on serum testosterone levels.

Combination dosing with Enz+Mif did not begin until after week 12 (which represents at least 12 weeks from baseline). In situations in which cycle 1 day 1 data was not available for baseline, the date of the pre-study PSA was used for dating testosterone baseline if patients were screened and started within a 5-day window. Post randomization data represents first testosterone value at least 4 weeks after week 12 testosterone level. Baseline testosterone levels were in the castrate range and did not significantly increase between baseline and Week 12. Combination dosing with Enz+Mif did not start until after week 12. Testosterone increased markedly after the addition of Mif in the Enz+Mif arm due to increased adrenal testosterone production. Testosterone did not substantially change for the group continuing to receive Enz alone. Star (*) represents p