Palliative systemic therapy for locally advanced or metastatic salivary duct carcinoma: A comprehensive review

Salivary duct carcinoma (SDC) is a rare and highly aggressive malignancy of the salivary glands. For patients ineligible for curative surgery or definitive radiotherapy, treatment options remain limited owing to the absence of standardized therapeutic protocols. This review draws upon major salivary gland cancer guidelines and integrates molecular profiles with clinical response data to propose an evidence-based treatment algorithm that stratifies patients into four groups according to the expression status of human epidermal growth factor receptor 2 (HER2) and androgen receptor (AR). In HER2-positive tumors, HER2-targeted therapy constitutes the standard of care, with trastuzumab plus docetaxel providing clinical benefit. Antibody-drug conjugates, such as trastuzumab deruxtecan, have demonstrated efficacy even in patients with disease progression during trastuzumab-based therapy. In AR-positive tumors, androgen deprivation therapy, particularly combined androgen blockade, has demonstrated clinical activity, though concurrent molecular characteristics may influence treatment outcomes. In HER2-positive/AR-positive tumors, HER2-targeted therapy is generally prioritized, although the absence of validated predictive biomarkers and defined thresholds remains a clinical challenge. For HER2-negative and AR-negative tumors, or those refractory to either or both targeted approaches, cytotoxic chemotherapy remains a viable option. Immune checkpoint inhibitors may offer benefits in tumors with high PD-L1 expression, although data on their role in SDC remain limited. Next-generation sequencing is recommended to identify actionable alterations (e.g., NTRK, BRAF, FGFR, HRAS) that may guide targeted therapy or clinical trial enrollment. Integrating comprehensive molecular profiling into treatment decision-making is essential to optimizing outcomes in advanced SDC.