Abstract 1397P
Background
Metastatic castration-resistant prostate cancer (mCRPC) remains an incurable disease with significant morbidity, despite the availability of multiple classes of therapies. Combining the selective glucocorticoid receptor (GR) modulator exicorilant (EXI) with the androgen receptor (AR) antagonist enzalutamide (ENZA) may block an important tumor escape pathway via dual antagonism of GR and AR. We report safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) results from the first study evaluating EXI + ENZA in patients with CRPC.
Methods
Segment 1 of this phase 1/2a dose-finding study (NCT03437941) evaluated open-label, twice-daily dosing of EXI. Patients (irrespective of prior ENZA exposure) received either EXI 180 mg BID + ENZA 160 mg QD, EXI 140 mg BID + ENZA 160 mg QD with a 28-day ENZA lead-in, or EXI 140 mg BID + ENZA 160 mg QD without an ENZA lead-in. Segment 2 evaluated QD dosing of EXI in a double-blind design in patients on a stable ENZA dose with rising PSA (25% increase over nadir and absolute value >1 ng/mL). All patients received EXI 240 mg QD + ENZA and were randomized 3:1 to EXI titration (to 280 mg followed by 320 mg) or to stay on EXI 240 mg. PK (EXI, ENZA) and PD (including cortisol and ACTH) were measured throughout the study.
Results
14 and 25 patients were enrolled in segments 1 and 2, respectively. 37 patients received at least one dose of EXI. Most frequent EXI-related adverse events (AEs) included fatigue (57%), back pain (35%), decreased appetite (27%), and neuropathic pain (22%). Dose-limiting toxicities were fatigue, musculoskeletal pain, and pancreatitis in segment 1, and fatigue, lipase increase, hypophosphatemia, AST/ALT/GGT increase, back pain, and vomiting in segment 2. EXI exposures were largely overlapping across dose levels in segment 2. No clinically relevant changes in the exposures of ENZA or its active metabolite, N-desmethyl ENZA, were observed when combined with EXI. ENZA exposures were consistent with historical data for ENZA 160 mg alone.
Conclusions
A maximum-tolerated dose of EXI in combination with ENZA was identified with fatigue and pain as the most common AEs. No clinically relevant changes were observed in ENZA exposure when given with EXI relative to ENZA alone.
Clinical trial identification
NCT03437941.
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
M. Linch: Financial Interests, Personal, Research Grant: AstraZeneca, BioNTech, Bristol Myers Squibb, Shionogi; Financial Interests, Personal, Other, Payment of honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events: AstraZeneca, BioNTech, Bristol Myers Squibb, Pfizer; Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb; Financial Interests, Personal, Other, Consulting fee: BioNTech, Pfizer, Astellas, Janssen, Bicycle Theraoeytucs, ADC therapeutics; Financial Interests, Personal, Other, support for attending meetings and/or travel: Bristol Myers Squibb. G. Liu: Financial Interests, Personal, Research Grant: Department of Defense CDMRP. S.J. Crabb: Financial Interests, Personal, Advisory Board: Roche, MSD, AstraZeneca, Astellas, Novartis, EMD, Bayer, Pfizer; Financial Interests, Personal, Invited Speaker: AstraZeneca, Astellas, Bayer, Janssen; Financial Interests, Personal, Expert Testimony: Pfizer/Merck, MSD; Financial Interests, Institutional, Funding: AstraZeneca, Astex Pharmaceuticals, Clovis Oncology, Roche; Financial Interests, Personal, Funding: AstraZeneca. T.M. Beer: Financial Interests, Institutional, Funding: Alliance Foundation Trials, Astellas Pharma, Bayer, Boehringer Ingelheim, Corcept Therapeutics, Endocyte Inc., Exact Sciences Corp, Freenome, Grail Inc., Harpoon Therapeutics, Janssen Research & Development, Medivation, Inc., Merck, Sotio, Theraclone Sciences/Onco Response, Zenith Epigenetics; Financial Interests, Personal, Advisory Role: AbbVie, Amgen, Arvinas, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Clovis Oncology, Constellation, Dantari Pharmaceuticals, GlaxoSmithKline, Grail Inc., Janssen, Myovant Sciences, Novartis, Pfizer, Sanofi, Sapience Therapeutics, Tolero; Financial Interests, Personal, Stocks/Shares: Arvinas Inc., Salarius Pharmaceuticals. E. Heath: Financial Interests, Personal, Other, Consulting/Advisory Role, Paid Travel: Astellas; Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Bristol Myers Squibb; Financial Interests, Personal, Other, Paid Travel: Caris Life Science; Financial Interests, Personal, Advisory Board, Speaker's Bureau, Paid Travel: Sanofi; Financial Interests, Personal, Advisory Board, Paid Travel: Seattle Genetics; Financial Interests, Institutional, Invited Speaker: Boeringer Ingelheim, Celldex, Corcept, Curemeta, Dendreon, eFFECTOR, Esanik, Fortis, Genenctech/Roche, Glaxo Smith Kline, Ignyta, Inovio, Medivation, Merck Sharpe Dohme, Merck, Millenium, Oncolys, Plexxikon, tokai, Zenith; Financial Interests, Personal, Other, Executive Committee Member Precision Oncology Alliance: Caris Life Science; Financial Interests, Personal, Invited Speaker: Seattle Genetics. M. Gordon: Financial Interests, Personal, Research Grant: Corcept Therapeutics. J.S. de Bono: Financial Interests, Personal, Advisory Board: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Financial Interests, Institutional, Advisory Board: Harpoon; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bayer, Cellcentric, Daiichi, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Vertex Pharmaceuticals, Sanofi Aventis, Sierra Oncology, Taiho, Crescendo Biologics; Non-Financial Interests, Principal Investigator: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Non-Financial Interests, Institutional, Product Samples: Daiichi, Bayer, Pfizer, Merck Serono, AstraZeneca, Harpoon, Sierra Oncology, Genentech/Roche, Sanofi Aventis, GlaxoSmithKline. H.I. Pashova: Financial Interests, Personal, Full or part-time Employment: of Corcept Therapeutics. I.C. Tudor, J.M. Custodio: Financial Interests, Personal, Full or part-time Employment: Corcept Therapeutics; Financial Interests, Personal, Stocks/Shares: Corcept Therapeutics. G. Mann: Financial Interests, Personal, Full or part-time Employment: Corcept Therapeutics. M.J. Morris: Financial Interests, Personal, Advisory Board: Oric, Pfizer, Exelixis, Lantheus, AstraZeneca, Amgen, Daiichi, Convergent; Financial Interests, Personal, Stocks/Shares: Doximity; Financial Interests, Institutional, Invited Speaker: Novartis, Corcept, Celgen, Janssen.