A phase 3, randomized, open-label study of INCB123667 versus investigator's choice of chemotherapy in patients with platinum-resistant ovarian cancer with cyclin E1 overexpression (MAESTRA 2, ENGOT-OV95, GOG-3137).

TPS5642 Background: Epithelial ovarian cancer (EOC) accounts for ~90% of ovarian cancers, with high-grade serous ovarian cancer (HGSOC) the most common histology. Despite high initial response rates to platinum-based therapy, ~70% of patients (pts) with advanced EOC relapse and nearly all recurrent disease ultimately becomes platinum resistant. Platinum-resistant ovarian cancer (PROC) remains a major therapeutic challenge with poor prognosis and limited treatment options. Standard therapies include single-agent, non-platinum chemotherapy with or without bevacizumab (bev), and mirvetuximab soravtansine (mirv) for pts with folate receptor alpha (FRα)-positive HGSOC. Approximately 50% of ovarian cancers overexpress cyclin E1. Cyclin E1 overexpression and increased cyclin-dependent kinase 2 (CDK2) activity are associated with poor outcomes and treatment resistance in ovarian cancer. A synthetic lethal relationship between CDK2 inhibition and cyclin E1 overexpression provides a strong biological rationale for selective CDK2 inhibition in this molecularly defined population. INCB123667 is a potent, selective, oral, small-molecule CDK2 inhibitor. In an ongoing phase 1 study, INCB123667 demonstrated manageable safety and objective response rates >30% in heavily pretreated pts with PROC and cyclin E1 overexpression [Damian S, et al. J Clin Oncol. 2025;43(16 suppl):5514; Simonelli M, et al. Ann Oncol. 2024;35(suppl 2):S495]. Methods: MAESTRA 2 (NCT07214779) is a global, multicenter, randomized, open-label phase 3 study evaluating the efficacy and safety of INCB123667 vs investigator’s choice chemotherapy (ICC) in ~466 female pts with platinum-resistant, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer with tumor cyclin E1 overexpression by immunohistochemistry (IHC; ≥75% of tumor cells with IHC score ≥1+). Eligible pts must have received 1-4 prior lines of systemic therapy, for whom single-agent chemotherapy is an appropriate next treatment. Pts should have received prior bev, and pts with FRα-positive disease should have received prior mirv. Pts are randomized 1:1 to INCB123667 50 mg twice daily or ICC (weekly paclitaxel, pegylated liposomal doxorubicin, gemcitabine, or topotecan). Randomization is stratified by primary platinum-free interval, ICC, and number of prior lines of systemic therapy. Dual primary endpoints are progression-free survival (PFS) by blinded independent central review (BICR) per RECIST v1.1 and overall survival. A key secondary endpoint is objective response by BICR per RECIST v1.1. Additional secondary endpoints include safety and tolerability, duration of response, PFS and objective response by investigator assessment, and health-related quality of life. The first pt was enrolled in Dec 2025. Clinical trial information: NCT07214779 .