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Approximately 50% of prostate cancer (PCa) patients harbor fusions involving the TMPRSS2 and ERG genes. Despite this, tailored therapies targeting the fused gene, tERG, remain undeveloped. Our study analyzed biopsy samples from two clinical trials assessing the efficacy of androgen receptor (AR) signaling inhibitors (ARSIs). The results revealed that tERG promotes resistance to ARSIs and is associated with elevated levels of the glucocorticoid receptor (GR). Subsequent assays showed that GR directly interacts with tERG, alleviates allosteric autoinhibition, and prevents chemotherapy-induced tERG degradation. In PCa models, either inhibiting GR or lowering cortisol levels suppressed tumor growth in tERG-positive models, but not in tERG-negative models. In addition, patient-derived fusion-positive xenografts displayed enhanced sensitivity to combined GR and AR inhibitors. Collectively, these findings highlight TMPRSS2-ERG as a new biomarker and propose that simultaneous inhibition of GR and AR may specifically benefit tERG-positive patients. However, GR stimulatory corticosteroid therapies may not be advisable for this patient subgroup.
BACKGROUND:Relacorilant is a selective glucocorticoid receptor modulator designed to reduce excess cortisol activity by competing with cortisol for glucocorticoid receptor binding, mitigating the clinical manifestations of endogenous hypercortisolism (Cushing's syndrome). The aim of this study was to assess the efficacy and safety of relacorilant in adults with endogenous hypercortisolism. METHODS:This multicentre, phase 3, double-blind, placebo-controlled, randomised-withdrawal study enrolled adults with endogenous hypercortisolism and hypertension, hyperglycaemia, or both and was conducted at 77 study centres across 11 countries. Key inclusion criteria included being aged 18-80 years with at least two clinical signs or symptoms of hypercortisolism. In the open-label phase, patients received oral, once-daily relacorilant (escalation from 100 mg up to 400 mg) for 22 weeks. Patients who met response criteria were randomly assigned (1:1) by the interactive web response system to continue relacorilant 400 mg (or highest tolerated dose) or placebo for 12 weeks in the randomised-withdrawal phase. Participants and investigators were masked to treatment assignment. The primary outcome was the proportion of patients who lost hypertension response during the randomised-withdrawal phase compared between relacorilant and placebo at week 12. As per protocol, this outcome was assessed in all participants who received at least one dose of study drug in the study period (intention-to-treat population). Missing randomised-withdrawal week 12 values were considered a loss of response. Safety was assessed in all enrolled patients who received at least one dose of study drug in that period. This study is registered with ClinicalTrials.gov, NCT03697109. FINDINGS:Between Oct 16, 2018, and April 15, 2024, 404 patients were screened, 152 were enrolled, and 95 completed the open-label relacorilant phase. 62 patients met response criteria and were randomly assigned to relacorilant (30 total participants [21 met hypertension response criteria]) or placebo (32 total participants [22 met hypertension response criteria]). In the 30 participants in the relacorilant group, the mean age was 46·6 years (SD 11·0), 22 (73%) were female, and eight (27%) were male. In the 32 participants in the placebo group, the mean age was 48·8 years (SD 14·4), 26 (81%) were female, and six (19%) were male. During the randomised-withdrawal phase, significantly more patients with baseline hypertension who were randomly assigned to placebo lost hypertension control compared with those who continued relacorilant (proportion difference 34%; odds ratio 0·17 [95% CI 0·04-0·77]; p=0·022). In the randomised-withdrawal phase safety population, the most common adverse events in the 30 participants given relacorilant and the 32 participants given placebo were back pain (5 [17%] vs 6 [19%]), acne (3 [10%] vs 0), arthralgia (3 [10%] vs 3 [9%]), bursitis (3 [10%] vs 0), headache (3 [10%] vs 4 [13%]), and insomnia (0 vs 4 [13%]). There were no cases of excessive glucocorticoid receptor antagonism, adrenal insufficiency, vaginal bleeding associated with endometrial hypertrophy, drug-induced hypokalaemia, or drug-induced QT interval prolongation. INTERPRETATION:Patients treated with relacorilant were more likely to maintain hypertension control compared with patients treated with placebo. The findings support consideration of relacorilant as a therapeutic option to reduce the harmful and debilitating effects of endogenous hypercortisolism. FUNDING:Corcept Therapeutics.
