Background: There is no standard first-line treatment for recurrent/metastatic (R/M) or unresectable locally advanced (LA) salivary gland cancer (SGC). Androgen receptor (AR) overexpression is known to be particularly high (43-92%) in SDC, depending on histology, and has been identified as a potential molecular target for SGC treatment. However, the clinical utility of this approach has not been well investigated. Here, we evaluated the efficacy and safety of darolutamide for patients with AR-positive SGC. Methods: Eligibility included LA or R/M, SGC histologically confirmed positive for AR by the central laboratory; PS 0-1; adequate organ function; and no suitable local therapy. The study consists of two sequential components: a monotherapy part with darolutamide alone (monotherapy part) and a combination part with darolutamide and goserelin (combination part). Darolutamide was given orally at 1,200 mg daily until disease progression or unacceptable toxicity. Primary endpoint for the monotherapy part was overall response rate (ORR) as determined by the investigator. Secondary endpoints were ORR by independent central review (ICR), clinical benefit rate (CBR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. (ClinicalTrials.gov NCT05694819). Results: From Mar 2020 to Jan 2021, 24 patients were enrolled in the monotherapy component. Median age was 64.6 years and 23 were male. ECOG PS was 0/1 in 18/6 cases. Pathological diagnosis was salivary duct carcinoma, adenocarcinoma NOS, and carcinoma ex pleomorphic adenoma in 16, 4 and 4 patients, respectively. ORR by investigator was 8.3% (90% CI 1.5–24.0) and ORR by ICR was 20.8% (95% CI 7.1–42.2). CBR and DCR were 41.7% (95% CI 22.1–63.4) and 58.3% (95% CI 36.6–77.9), respectably. Median PFS and OS were 5.7 months (95% CI, 1.9–15.2) and not reached (95% CI, 15.5–not estimable [NE]), respectively, with a median follow-up period of 19.1 months. Nine patients (37.5%) had grade 3 or 4 treatment-related adverse events. There were no treatment-related fatal adverse events. Conclusions: This is the first prospective trial of darolutamide for AR-positive SGC. The response rate by ICR and other secondary endpoints confirmed clinically meaningful activity and a well-tolerated safety profile. Patient enrollment to the combination component is now ongoing to evaluate additional benefits. Clinical trial information: NCT05694819.