Current perspectives in the pharmacological combination treatment for low-grade serous ovarian cancer

Low-grade serous ovarian carcinoma (LGSOC) is a rare, frequently relapsing ovarian cancer characterized by relative chemoresistance, hormone-receptor expression, and recurrent activation of the RAS/RAF/MEK/ERK pathway.

This narrative review examines the therapeutic vulnerabilities that are reshaping systemic treatment in LGSOC. PubMed/MEDLINE and Embase were searched from database inception through July 2026, supplemented by clinical-trial registries and regulatory sources. Endocrine dependence can be targeted with aromatase inhibitors and, increasingly, through combined estrogen-receptor and CDK4/6 blockade. MAPK signaling represents the principal molecular vulnerability: trametinib provides the strongest randomized evidence in recurrent disease, while avutometinib plus defactinib is approved in the United States for previously treated KRAS-mutated LGSOC. The review also considers the evolving role of chemotherapy, antiangiogenic therapy, and molecular biomarkers in treatment selection.

The therapeutic landscape is moving from empiric chemotherapy toward biologically informed treatment. The main challenge is now to define the optimal sequence of endocrine, MAPK-directed, and cell-cycle-targeted therapies according to disease tempo, molecular profile, required tumor shrinkage, prior exposure, and cumulative toxicity. Emerging strategies include combined pathway inhibition, chemotherapy-sparing endocrine regimens, and antibody-drug conjugates directed against FRα and TROP2. Their future integration will require prospective biomarker validation and direct comparison with established active treatments.