Neoadjuvant androgen deprivation therapy with enzalutamide plus the glucocorticoid receptor modulator relacorilant versus placebo for patients with high-risk localized prostate cancer.

TPS436 Background: Despite definitive local treatment, high risk localized prostate cancer (PC) patients (pts) have a 36-46% risk of biochemical recurrence (1). Neoadjuvant (NAJ) treatment with androgen receptor signaling inhibition (ARSI) improves pathologic outcome at the time of prostatectomy (2), and 3-year biochemical recurrence-free survival (bRFS) was strongly tied to pathologic complete response (pCR) plus minimal residual disease (MRD). One way to improve on this strategy is to target potential mechanisms of resistance to ARSI. A study of localized high-risk prostate cancer treated with NAJ ARSI plus androgen deprivation therapy (ADT) showed enrichment of glucocorticoid receptor (GR) expression in residual tumors (3). Inhibiting GR signaling decreases resistance to the ARSI enzalutamide (4). We previously demonstrated the safety of the combination of the selective GR modulator (SGRM) relacorilant plus enzalutamide (5). We have thus designed a study evaluating the efficacy of this combination given neoadjuvantly. Methods: This phase 2 study is a placebo-controlled randomized trial of 6 months of NAJ ADT and enzalutamide plus relacorilant/placebo (2:1). The primary objective of this study is response, measured by pCR and MRD at radical prostatectomy (RP). Eligible patients include those with localized histologically confirmed prostatic adenocarcinoma classified as high risk or very high-risk per NCCN guidelines. Enlarged lymph nodes below the iliac bifurcation are allowed. Following randomization pts will be treated with LHRH agonist plus enzalutamide with or without relacoriliant and undergo RP 1 month later. The total sample size is 90 patients with an interim analysis for futility conducted after 45 pts undergo RP. A chi-square test will be used to compare the proportion of patients achieving pCR/MRD. Assuming a true CR/MRD rate of 15% in the control group, 90 patients total would yield a power of 80% with a hypothesized CR/MRD of 32% in the relacorilant group, based on a one-sided test at the alpha=0.15 significance level. As secondary endpoints, we will evaluate radiographic response within the prostate with multiparametric MRI (mpMRI) imaging and the 3-year bRFS and MFS rates in both arms. Exploratory endpoints include demonstrating correlation between enhanced mpMRI imaging and pathologic response, as well showing decreased nuclear hormone receptor-driven proliferative gene expression in viable PC due to combined NAJ GR antagonism and ARSI compared to ARSI alone. The study is currently open and is seeking additional sites. 1. Falgario U, JAMA Netw Open 2023. 2. McKay R, J Urol 2021. 3. Efstathiou E, Eur Urol 2019. 4. Isikbay M, Horm Cancer 2014. 5. Desai, CCR , 2024. Clinical trial information: NCT05726292 .