Cyclin-dependent kinase 4/6 inhibitors in granulosa cell tumors and their combination with hormonal therapy: a scoping review.

Background: Adult granulosa cell tumor (aGCT) is a rare ovarian malignancy with frequent late recurrences and limited systemic treatment options. Emerging evidence suggests that dysregulation of the cyclin D-cyclin-dependent kinase (CDK) 4/6-retinoblastoma (Rb) axis contributes to aGCT biology, while hormone receptor expression supports the potential role of endocrine therapy. We performed a scoping review to map available evidence on CDK4/6 inhibition in aGCT. Methods: A literature search was conducted in PubMed/MEDLINE, Embase and Web of Science, complemented by searches of trial registries, conference abstracts and citation searching. Eligible reports included translational, preclinical and clinical studies addressing CDK4/6 pathway dysregulation or CDK4/6 inhibition in aGCT. Evidence on endocrine therapy was synthesized narratively to contextualize combination strategies. Results: Twenty-three reports were included. Translational and genomic studies showed recurrent abnormalities affecting cell-cycle regulation, including alterations in CDK inhibitors, Rb-associated signaling and other proliferation-related pathways. Preclinical studies demonstrated that CDK4/6 inhibition, particularly with abemaciclib, reduced cell viability and tumor growth in GCT models. Clinical evidence was limited to small retrospective case series, which suggested clinically meaningful disease control in a subset of patients with recurrent disease. An ongoing phase II trial is expected to provide the first systematic evaluation of this therapeutic strategy. Conclusions: Available evidence supports CDK4/6 inhibition as a biologically plausible therapeutic strategy in aGCT. Although current clinical data remain limited, the combination of CDK4/6 inhibitors with endocrine therapy appears promising and warrants prospective evaluation.