BackgroundSalivary duct carcinoma (SDC) and adenocarcinoma, not otherwise specified (adeno‐NOS), are rare salivary gland cancers. Data on the efficacy of systemic therapy for these diseases are limited.MethodsData were retrospectively collected from patients seen at The University of Texas MD Anderson Cancer Center during 1990 to 2020. Objective response rate (ORR) was assessed per RECIST v1.1. Recurrence‐free survival (RFS), progression‐free survival (PFS), and overall survival (OS) were assessed by Kaplan‐Meier method. Cox regression model was performed to identify predictors of survival.ResultsThe analysis included 200 patients (110 with SDC and 90 with adeno‐NOS); 77% had androgen‐receptor‐positive tumors and 47% had HER2‐positive (2+‐3+) tumors. Most patients without metastasis at diagnosis underwent surgery (98%) and postoperative radiotherapy (87%). Recurrence rate was 55%, and the median RFS was 2 years. Nodal involvement and positive surgical margins were associated with recurrence (P < .005). Among patients with stage IVA‐B disease, addition of systemic therapy to local therapy increased OS (P = .049). The most‐used palliative‐systemic‐therapy regimen was platinum doublet ± trastuzumab. For first‐line therapy, the ORR and median PFS were 33% and 5.76 months, respectively, and for second‐line therapy the ORR and median PFS were 25% and 5.3 months, respectively. ORR and PFS were higher with HER2‐targeting agents. Median OS was 5 years overall and 2 years for metastatic disease. Older age and higher stage were associated with worse OS.ConclusionAdding systemic therapy to local therapy may improve outcomes of patients with locoregionally advanced SDC or adeno‐NOS. Except for HER2‐targeted therapy, response to palliative systemic therapy is limited. These findings may be used as a benchmark for future drug development.