A phase 2 study of darolutamide plus leuprolide acetate in hormone therapy–naïve recurrent and/or metastatic androgen receptor (AR)–positive salivary gland cancer (ETCTN 10553).

6012 Background: A subset of salivary gland cancers (SGCs) express the androgen receptor (AR). A prior AR+ SGC trial with the anti-androgen enzalutamide alone failed to meet its primary endpoint. This is a multicenter, phase II study evaluating the efficacy and safety of the anti-androgen darolutamide (Bayer) in combination with androgen-deprivation therapy (ADT; leuprolide acetate) in hormone-therapy naïve patients with AR+ SGCs. Methods: Patients with locally advanced/unresectable or recurrent/metastatic AR+ SGCs were enrolled. AR status was determined locally by immunohistochemistry (IHC). Prior AR-targeted therapy was not allowed, unless administered in the neoadjuvant and/or adjuvant setting >6 months before disease recurrence. Darolutamide 600 mg orally twice daily was given with leuprolide acetate intramuscular injections (1 cycle= 28 days). The primary endpoint was best overall response (BOR) rate according to RECIST v1.1 within 1 year of initiating treatment. Secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. Exploratory endpoints were evaluating biomarkers in serially obtained research biopsies and exploring efficacy among patients who had not received prior systemic therapy. A two-stage minimax design was used to detect a 50% BOR rate (vs. 25%) (alpha = 9%; beta = 83%). ≥3 responses in the first 9 patients would trigger accrual to 20; ≥8 responses would be considered promising. Results: Study accrual of 20 patients (pts) with AR+ SGCs was completed on 10/30/25. 15 males, 5 females with a median age of 70.5 years were enrolled. Among the 9 pts in the first stage, 6 confirmed partial responses (PRs) were observed, allowing for full study accrual. With a data cutoff of 1/21/26, the best RECIST v1.1 responses among 20 pts were 8 (40% [19.1% 63.9%]) PRs (7 confirmed, 1 unconfirmed with pt still on treatment), 10 (50% [27.2%, 72.8%]) stable disease (SD), 1 (5% [1%, 24.9%]) progression of disease; 1 pt on treatment has not had radiographic assessments yet. 6 (30% [11.9%, 54.3%]) pts came off trial for disease progression, 1 (5% [1%, 24.9%]) withdrew consent after 6 cycles, and 13 (65%, [40.8%, 84.6%]) remain on treatment. Among 5 female pts, best responses were 1 (5% [1%, 24.9%]) PR, 3 (15% [3.2%, 37.9%]) SD, 1 (5% [1%, 24.9%]) PD. With additional follow-up, PFS, OS, and biomarker data (AR IHC %, HER2 status) will be presented. Conclusions: In this molecularly selected cohort of patients with SGC, darolutamide plus ADT possesses significant clinical activity, validating AR as a relevant therapeutic target in a subset of SGCs. Analysis of serial research biopsies will be performed to identify biomarker and/or drug combination strategies to enhance the efficacy of AR-targeting. Clinical trial information: NCT05669664 .