What does this research mean for the field?

Neoadjuvant treatment with LHRH agonist/antagonist, enzalutamide, and the glucocorticoid receptor antagonist relacorilant improves pathologic complete response and minimal residual disease rates in high-risk localized prostate cancer compared to placebo. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

To evaluate the efficacy of relacorilant with enzalutamide in improving pathologic complete response in high-risk localized prostate cancer.

March 4, 2026

High-risk localized prostate cancer treated with neoadjuvant LHRH agonist/antagonist and enzalutamide plus the glucocorticoid receptor antagonist relacorilant versus placebo.

Puntos clave

To evaluate the efficacy of relacorilant with enzalutamide in improving pathologic complete response in high-risk localized prostate cancer.
Conducting a phase 2, placebo-controlled, randomized trial with a 2:1 allocation.
Participants receive 6 months of LHRH agonist/antagonist, enzalutamide, and either relacorilant or placebo.
Primary endpoint focused on pathologic complete response and minimal residual disease after radical prostatectomy.
Statistical analysis includes chi-square test for difference in treatment response.
Interim analysis for futility after 45 patients undergo surgery.
Of 90 planned participants, 30 have enrolled as of October 2025.
Initial follow-up includes 23 participants, while 7 are still receiving treatment.
The hypothesized pathologic response combination is expected to yield a significant improvement compared to the control group's estimated rate.

Resumen

TPS415 Background: Of the estimated 31,000 high risk localized prostate cancer (PC) cases in 2025, up to 46% have a risk of biochemical recurrence after definitive treatment (Falgario U, JAMA Netw Open 2023). A pooled analysis showed 3-year biochemical recurrence-free survival (bRFS) was robustly correlated to pathologic complete response (pCR) plus minimal residual disease (MRD) in patients treated neoadjuvantly (NAJ) with androgen deprivation therapy (ADT) plus an androgen receptor pathway inhibitor (ARPI) (McKay R, J Urol 2021). A separate study of localized high-risk PC revealed increased glucocorticoid receptor (GR) expression in residual tumors of PC patients (pts) treated with NAJ ARPI plus ADT (Efstathiou E, Eur Urol 2019). Resistance to the ARPI enzalutamide (Enz) is mitigated by targeting GR (Isikbay M, Horm Cancer 2014). We previously demonstrated the safety of the combination of the selective GR antagonist (SGRA) relacorilant (Rel) plus Enz (Desai, CCR , 2024). We have thus initiated a trial to evaluate the NAJ efficacy of this combination. Methods: This phase 2 placebo-controlled 2:1 randomized trial of NAJ LHRH agonist/antagonist and Enz (160 mg daily) plus Rel (150 mg daily)/placebo has a primary objective of response, measured by pCR and MRD at radical prostatectomy (RP). Eligible pts include those with high risk or very high-risk localized prostatic adenocarcinoma per NCCN guidelines, allowing lymph nodes below the iliac bifurcation. After randomization pts will be treated with 6 mo of LHRH agonist/antagonist plus Enz plus Rel/placebo 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. As of October 2025, 30 pts have enrolled, with 23 in follow up and 7 on treatment. A chi-square test will be used to compare the proportion of pts achieving pCR/MRD. Assuming a true CR/MRD rate of 15% in the control group, 90 pts total would yield a power of 80% with a hypothesized CR/MRD of 32% in the Rel group, based on a one-sided test at the alpha=0.15 significance level. Secondary endpoints include evaluating radiographic response within the prostate with multiparametric MRI (mpMRI) and the 3-year bRFS and metastasis-free survival (MFS) rates in both arms. For correlatives, we will demonstrate decreased nuclear hormone receptor-driven proliferative gene expression in viable PC due to NAJ ARPI combined with GR antagonism versus ARPI alone, as well as correlation between pathologic response and enhanced mpMRI imaging. The study is open and seeking additional sites (currently 3 open). ClinicalTrials.gov Identifier: NCT05726292. Clinical trial information: NCT05726292 .

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