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Exicorilant in mCRPC: a fourth failure for the GR-bypass hypothesis

OncologyEfficacyMay 17th, 2026·6 min read·10.5281/zenodo.20301169

Mechanism Risk Score

ComponentPoints
Phase-weighted failure burden6.8 / 40
Archetype severity9.8 / 25
Temporal recency4.3 / 15
Genetic evidence deficit7.0 / 15
Programmatic saturation2.5 / 5

For NR3C1 in Metastatic Castration-Resistant Prostate Cancer, the Mechanism Risk Score is 30/100 (yellow band). The score is a failure-burden index derived from Claidex post-mortems on this target–disease pair, not a probability of approval.

MRS 30/100 (YELLOW). 1 programs across NR3C1 have been documented for NR3C1 in Metastatic Castration-Resistant Prostate Cancer: 0 Phase 3, 1 Phase 2, 0 Phase 1 — of which 1 were efficacy failures, 0 safety, 0 biomarker, and 0 operational (enrollment, sponsor, or funding). The most informative failure on file is Exicorilant in mCRPC: a fourth failure for the GR-bypass hypothesis. This score quantifies the documented failure burden; the Open Targets association score of 0.53 reflects moderate genetic support, neither rescuing nor compounding the failure record. The MRS is not a prediction of future trial outcomes — it is a structured summary of the empirical record, recomputed live from the Claidex claims table, and intended to flag mechanisms where any new program must explicitly resolve each prior failure mode before pursuit is justified.

This score does not predict whether the next trial will succeed. It flags how heavy the documented mechanistic failure record is before a new program is justified.

What was tried

Corcept Therapeutics ran a Phase 1/2a study of exicorilant, a selective glucocorticoid receptor antagonist, combined with enzalutamide in metastatic castration-resistant prostate cancer. NCT03437941 enrolled thirty-nine patients across seven dose-finding arms in two segments. Results posted on May 15, 2026 confirmed the termination: "the level of benefit observed did not justify enrolling patients in the Dose Expansion phase of the study."

The biological hypothesis

The trial rested on an influential preclinical story. In 2013, Arora and colleagues at MSKCC showed that enzalutamide-resistant prostate cancer cells upregulate the glucocorticoid receptor (GR), and that GR drives a substantially overlapping transcriptional program. A GR agonist conferred resistance, a GR antagonist restored sensitivity. AR normally represses GR at the GR locus, and acute AR blockade relieves that repression, letting a primed subset of cells drive AR target genes via an alternative nuclear receptor.

Follow-up in 2017 showed this GR upregulation is adaptive and reversible, controlled by a tissue-specific enhancer, and that BET bromodomain inhibition can disable the escape. The rationale was strong enough to launch four clinical programs in CRPC, three using an enzalutamide combination.

What actually happened

Across the seven dose cohorts, two of thirty-nine patients had confirmed objective responses and six of thirty-nine met the PSA50 threshold. The dose-titration arms in Segment 2 showed median times to PSA progression of 1.41 to 3.25 months. Only Cohort 3 (280 mg exicorilant, no enzalutamide lead-in) produced meaningful activity, with three of seven patients reaching PSA50 and a median time to PSA progression of 38.9 months. That cohort is also the only one in which patients were not pre-progressing on enzalutamide. The signal that looked best was the signal least informative about the GR-bypass hypothesis.

This is the fourth GR-antagonist program to land here. Taplin 2008 gave mifepristone monotherapy to nineteen CRPC patients with zero PSA50 responses, while adrenal androgens rose by ninety-one percent. Serritella 2022 randomized 106 patients to enzalutamide with or without mifepristone and stopped for futility on PFS. Abida 2024 ran ORIC-101 plus enzalutamide in forty-one patients, missed its twelve-week disease control target, and terminated. Four trials, eighteen years, no expansion cohort opened.

Four GR antagonist trials in metastatic CRPC, eighteen years, zero expansions. Sources: ClinicalTrials.gov NCT03437941, PMIDs 18399827, 35110415, 38226958.

Failure mechanism, best guess

Two parsimonious explanations.

First, tumor heterogeneity and timing. The Arora model describes one resistance mechanism in one fraction of cells. By the time a patient has progressed on second-generation AR inhibitors, multiple escape routes are running in parallel: AR-V7 splice variants, neuroendocrine lineage plasticity, FGFR upregulation, MYC amplification. Epigenetic profiling of mCRPC tumors finds parallel chromatin programs in endocrine-resistant disease. Reversing the GR fraction does not restore enzalutamide sensitivity in the rest of the tumor. The Cohort 3 signal, which selected enzalutamide-naive patients, fits this. Activity shows up before the polyclonal landscape consolidates.

Second, the pharmacology is leakier than the preclinical models assumed. Mifepristone raises adrenal androgens via HPA feedback (Taplin 2008 showed a ninety-one percent testosterone rise). Selective antagonists like exicorilant and ORIC-101 were designed to avoid that loop, and Abida 2024 confirmed pharmacodynamic target engagement in peripheral biomarkers. Engagement in blood is not the same as inhibition in tumor tissue, where FOXA1-restricted chromatin accessibility makes GR activity context-dependent and hard to read peripherally.

A third explanation is harder to rule out: GR antagonism may work only in a small biomarker-defined subset. Abida 2024 saw exploratory benefit in patients with high GR expression and no other resistance markers. None of the four trials enriched prospectively for that subset.

What this means for similar programs

Relacorilant in mCRPC (Desai 2024) reported Phase I without a Phase II launch, and Corcept has shifted relacorilant toward ovarian cancer. ORIC-101 has been discontinued in prostate (NCT04033328). The dual AR-GR antagonism hypothesis in late-line CRPC should be considered closed. Worth watching: upstream BET inhibition (Shah 2017 predicted it disables the GR enhancer) and GR-FOXA1 axis targeting in NSCLC subsets where the chromatin context looks more tractable.

Open questions

  • Does GR antagonism work in mCSPC or first-line mCRPC, before polyclonal resistance consolidates?
  • Does prospective enrichment for GR-high, AR-V7-negative tumors produce a registration-worthy signal?
  • Is the GR-LEDGF/p75-HSP27 axis (Ochoa 2025) a more druggable choke point than GR itself?

Sources

  1. Arora VK, Schenkein E, Murali R, Subudhi SK, Wongvipat J, Balbas MD, et al.. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell. 2013;155(6);1309-1322. PMID: 24315100.

  2. Shah N, Wang P, Wongvipat J, Karthaus WR, Abida W, Armenia J, et al.. Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer. Elife. 2017;6. PMID: 28891793.

  3. Taplin ME, Manola J, Oh WK, Kantoff PW, Bubley GJ, Smith M, et al.. A phase II study of mifepristone (RU-486) in castration-resistant prostate cancer, with a correlative assessment of androgen-related hormones. BJU Int. 2008;101(9);1084-1089. PMID: 18399827.

  4. Serritella AV, Shevrin D, Heath EI, Wade JL, Martinez E, Anderson A, et al.. Phase I/II Trial of Enzalutamide and Mifepristone, a Glucocorticoid Receptor Antagonist, for Metastatic Castration-Resistant Prostate Cancer. Clin Cancer Res. 2022;28(8);1549-1559. PMID: 35110415.

  5. Abida W, Hahn AW, Shore N, Agarwal N, Sieber P, Smith MR, et al.. Phase I Study of ORIC-101, a Glucocorticoid Receptor Antagonist, in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer Progressing on Enzalutamide. Clin Cancer Res. 2024;30(6);1111-1120. PMID: 38226958.

  6. Desai KB, Serritella AV, Stadler WM, O'Donnell PH, Sweis RF, Szmulewitz RZ. A Phase I Trial of Enzalutamide Plus Selective Glucocorticoid Receptor Modulator Relacorilant in Patients with Metastatic Castration-Resistant Prostate Cancer. Clin Cancer Res. 2024;30(11);2384-2392. PMID: 38536082.

  7. Helminen L, Huttunen J, Tulonen M, Aaltonen N, Niskanen EA, Palvimo JJ, et al.. Chromatin accessibility and pioneer factor FOXA1 restrict glucocorticoid receptor action in prostate cancer. Nucleic Acids Res. 2024;52(2);625-642. PMID: 38015476.

  8. Severson TM, Minnee E, Zhu Y, Schuurman K, Nguyen HM, Brown LG, et al.. Epigenetic profiling identifies markers of endocrine resistance and therapeutic options for metastatic castration-resistant prostate cancer. Cell Rep Med. 2025;6(7);102215. PMID: 40609538.

  9. Ochoa PT, Sanchez-Hernandez ES, Duran AM, Cheng KW, Philip J, Suzuki T, et al.. The GR-LEDGF/p75-HSP27 Axis Contributes to Cross-Resistance Between Enzalutamide and Docetaxel in Prostate Cancer. Cells. 2025;14(19). PMID: 41090793.

  10. Dorso M, Patel PT, Pankov A, Boyer JA, Soni RK, Del Priore IS, et al.. A Druggable FOXA1-Glucocorticoid Receptor Transcriptional Axis Drives Tumor Growth in a Subset of Non-Small Cell Lung Cancer. Cancer Res Commun. 2023;3(9);1788-1799. PMID: 37691854.

  11. Taya M, Hou X, Veneris JT, Kazi N, Larson MC, Maurer MJ, et al.. Investigation of selective glucocorticoid receptor modulation in high-grade serous ovarian cancer PDX models. J Gynecol Oncol. 2025;36(1);e4. PMID: 38909640.

  12. ClinicalTrials.gov. NCT03437941. Study to Evaluate Exicorilant (CORT125281) in Combination With Enzalutamide in Patients With mCRPC. Results posted 2026-05-15. https://clinicaltrials.gov/study/NCT03437941.

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