Background: Adult ovarian granulosa cell tumours (GCT) are the most common subtype of ovarian sex cord-stromal tumours. Forkhead transcription factor FOXL2 is required for development and function of normal granulosa cells, including proliferation and ovarian hormone synthesis. A single somatic missense mutation in FOXL2, c.402C > G (p.Cys134Trp), has previously been identified in the majority of GCT and is a pathognomonic marker for this tumour type. NOTCH activation contributes to GCT survival in preclinical models, and NOTCH2 and NOTCH3 are critical for embryonic development of the ovary and function of the ovarian follicle. Nirogacestat is a potent, selective, noncompetitive inhibitor of gamma secretase, which inhibits NOTCH pathway signalling. Treatment of GCT with nirogacestat was predicted to inhibit granulosa cell survival.
Methods: A Phase II clinical trial was conducted to assess antitumour activity of nirogacestat in adult patients with relapsed/refractory ovarian GCT (NCT05348356). This study enrolled 53 patients; all were evaluable for efficacy and safety. Endpoints included objective response rate by Response Evaluation Criteria in Solid Tumors v1.1 and 6-month progression-free survival (PFS6). Fresh or archival tumour samples were analysed for mutational profiling.
Results: Patients received a median of 5 prior lines of therapy (range, 1-13) and a median of 3.7 months of treatment (range, 0-20 months). A decrease in tumour burden was seen in 16 (30%) patients; however, there were no confirmed objective responses. Thirty-one (58%) patients had stable disease; 18 (34%) had progressive disease. Eleven (21%) patients achieved PFS6. No correlations with disease stability were found with baseline clinical characteristics. All 3 patients who had an activating NOTCH1 mutation achieved PFS6.
Conclusions: In patients with heavily pretreated GCT, nirogacestat treatment resulted in durable disease stabilisation of at least 7 weeks for 58% of patients, with 21% achieving PFS6, including the 3 patients whose tumours had an activating NOTCH1 mutation.
Key points: This Phase II clinical trial of a rare tumour achieved its enrolment target in under 1 year and completed primary analysis within 2 years. 87% (46 of 53 patients who received nirogacestat) had fresh or archival biopsies that were analysed by next-generation sequencing for mutational profiling. Of the 3 patients with activating NOTCH1 mutations, all achieved 6-month progression-free survival (PFS6); 8 other patients also achieved PFS6 but did not share a common mutation.
Keywords: NOTCH; gamma secretase inhibitors; mutational profiling; tumour recurrence.
© 2026 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.