524MO - Glucocorticoid receptor expression and activity in a phase II ovarian cancer trial of the glucocorticoid receptor modulator relacorilant in combination with nab-paclitaxel

Background

Cortisol activity at the glucocorticoid receptor (GR) contributes to chemotherapy resistance by suppressing apoptotic pathways that taxanes utilize, and high tumor GR expression is associated with poor chemotherapy response in ovarian cancer. A phase 2 ovarian cancer study (NCT03776812) demonstrated the clinical benefit of adding relacorilant (RELA), a selective GR modulator, to nab-paclitaxel (NP) compared to NP alone. We present biomarker analyses from this study.

Methods

A phase 2, open-label, randomized study of RELA in combination with NP compared with NP alone was conducted in patients with ovarian cancer. 127 formalin-fixed paraffin-embedded tumor samples collected as part of the study were analyzed using a CLIA-validated GR immunohistochemistry (IHC) assay. RNA expression was measured in whole blood using a custom NanoString^TM panel focused on GR target genes.

Results

Tumor GR expression (IHC H-score >0) was observed in 96% (122/127) of tumor samples. High tumor GR expression (H-score ≥100) was observed in 65% (82/127) of samples and associated with non-response to NP-only (stable or progressive disease). In contrast, high GR expression was associated with good response (partial or complete response) in patients receiving RELA + NP (χ² P= 0.037). Subjects with low baseline plasma TGF-β1 (<30,000 pg/mL) treated with RELA + NP had significantly longer overall survival (OS) compared to those with high TGF-β1 (P<0.0001). Of 239 genes previously shown to be GR target genes, 221 were suppressed after RELA + NP treatment. Significantly fewer GR target genes were suppressed by NP (P<0.00001). GR target genes that were suppressed by RELA + NP but not NP alone included SGK1 (P=0.013), PIK3CG (P=0.018), and GSK3B (P=0.05).

Conclusions

GR expression was abundant in the ovarian tumors assessed in this study. High GR expression was associated with poor outcomes in patients treated with NP alone. In contrast, high baseline tumor GR expression was associated with good response in patients treated with RELA + NP. Low plasma TGF-β1 predicted longer OS. Suppression of GR-target genes indicated systemic GR antagonism by RELA.

Clinical trial identification

NCT03776812.

Editorial acknowledgement

Writing and editorial support for this abstract was provided by Tina Schlafly, PhD, an employee of Corcept Therapeutics.

Legal entity responsible for the study

Corcept Therapeutics.

Funding

Corcept Therapeutics.

Disclosure

D. Lorusso: Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speaker: GSK, Clovis Oncology, PharmaMar; Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speakers: AstraZeneca, MSD; Financial Interests, Personal, Other, Consultancy: PharmaMar, Amgen, AstraZeneca, Clovis Oncology, GSK, MSD, Immunogen, Genmab, Seagen; Financial Interests, Personal, Advisory Board, Participation in Advisory Boards: Merck Serono; Financial Interests, Personal, Advisory Board, Invited member of advisory board: Seagen, Immunogen, Genmab, Oncoinvest, Corcept, Sutro; Financial Interests, Institutional, Funding, Grant for funding academic trial: MSD, Clovis Oncology, PharmaMar; Financial Interests, Institutional, Funding, Grant for founding academic trial: GSK; Financial Interests, Institutional, Invited Speaker, ENGOT trial with institutional support for coordination: Clovis Oncology; Financial Interests, Institutional, Invited Speaker, ENGOT trial with insitutional support for coordination: Genmab, MSD; Financial Interests, Institutional, Funding, Clnical trial/contracted research: AstraZeneca, Clovis Oncology, GSK, MSD, Seagen; Financial Interests, Institutional, Funding, Clinical trials/contracted research: Genmab, Immunogen, Incyte, Novartis, Roche; Non-Financial Interests, Principal Investigator, PI of several trials, no compensation received: GSK; Non-Financial Interests, Principal Investigator, PI of several trials. No personal compensation received: AstraZeneca, Genmab; Non-Financial Interests, Principal Investigator, PI in several trials. No personal compensation received: MSD; Non-Financial Interests, Principal Investigator, PI of clinical trial. No personal compensation received: immunogen, clovis, Incyte; Non-Financial Interests, Principal Investigator, PI of clinical trial. No personal compensation receive: roche; Non-Financial Interests, Member, Board of Directors: GCIG. A.E. Greenstein: Financial Interests, Personal, Project Lead, Employee: Corcept Therapeutics; Financial Interests, Personal, Stocks/Shares: Corcept Therapeutics. S.A. Wadekar: Financial Interests, Personal, Other, Employee: Corcept Therapeutics. I.C. Tudor: Financial Interests, Personal, Project Lead, Employee: Corcept Therapeutics. H.J. Hunt: Financial Interests, Personal, Officer: Corcept Therapeutics. B. Guyer: Financial Interests, Personal, Officer: Corcept Therapeutics.