SpringWorks Therapeutics' Ogsiveo Shows No Objective Responses in Phase 2 for Ovarian Granulosa Cell Tumors
Phase 2 Trial Concluded Without Objective Responses
SpringWorks Therapeutics (formerly NASDAQ:SWTX) completed a single-arm, open-label Phase 2 trial (NCT05348356) of Ogsiveo (nirogacestat) in patients with recurrent/refractory adult-type ovarian granulosa cell tumors (OvGCT). A total of 53 patients across 16 sites in the U.S. and Poland received 150 mg of nirogacestat twice daily. The median prior systemic therapy was five lines, ranging from one to thirteen. While tumor burden decreased in 16 patients (30%), no confirmed complete or partial responses were observed according to RECIST 1.1 criteria, resulting in a 0% objective response rate (ORR), the primary endpoint. The results indicate clear efficacy limitations for a monotherapy approach emphasizing tumor shrinkage.
Signals of Disease Stabilization with Limited Durability
Thirty-one patients (58%) achieved stable disease (SD) for at least seven weeks, and 11 patients (21%) achieved progression-free survival at six months (PFS6). However, 18 patients (34%) were assessed as having progressive disease, and the median treatment duration was only 3.7 months, suggesting that SD alone is insufficient to establish clinical utility. Although the enrolled population had heavily pretreated patients, subsequent trials for regulatory approval would need to demonstrate objective responses or improvements in progression-free survival compared to a control group. These data are more exploratory in nature, likely prompting a reevaluation of combination strategies and patient selection rather than immediate regulatory pathways.
Biological Signals Targeting NOTCH
Ogsiveo is an oral small molecule that selectively and non-competitively inhibits gamma-secretase to block NOTCH signaling. Among 46 patients with available next-generation sequencing data, all three patients with activating NOTCH1 mutations achieved PFS6, but no common mutations were identified among the remaining eight PFS6 responders. With only three samples, this is insufficient to establish companion diagnostics or predictive biomarkers, suggesting the need for a prospectively stratified cohort targeting NOTCH1-mutant patients. Conversely, the analysis of multiple survival pathways provides a biological rationale for combining nirogacestat with hormonal therapy or other targeted treatments rather than expanding it as monotherapy.
Competitive Landscape, Market Potential, and Regulatory Context
For recurrent OvGCT, treatment options beyond tumor resection include the BEP chemotherapy regimen (bleomycin, etoposide, cisplatin), aromatase inhibitor Arimidex (anastrozole, targeting estrogen synthesis), and Roche’s Avastin (bevacizumab, targeting VEGF-A). Compared to the 16.7% ORR reported in bevacizumab monotherapy trials, nirogacestat’s 0% ORR appears less competitive. The global ovarian cancer treatment market is projected to grow from $3.8999 billion in 2024 to $5.6546 billion by 2030, but the commercial potential for the rare histology of OvGCT remains limited. Ogsiveo is a marketed product approved by the FDA on November 27, 2023, and by the EU on August 14, 2025, for progressive desmoid tumors, but it is not approved for OvGCT. SpringWorks was acquired by Merck KGaA on July 1, 2025.
From an investor perspective, the Phase 2 ORR of 0% and a median treatment duration of 3.7 months weaken the rationale for expanding Ogsiveo’s indication into the $3.8999 billion 2024 global ovarian cancer treatment market. In the short term, the lack of differentiation compared to BEP chemotherapy, aromatase inhibitors like Arimidex, and Avastin with a 16.7% ORR suggests that reevaluating development priorities is more rational than pursuing a separate regulatory trial. From a research standpoint, the achievement of PFS6 in all three NOTCH1-mutant patients supports the design of prospective biomarker cohorts and combination trials, although the overall PFS6 rate remains at 21%. The mid-to-long-term value hinges on Merck KGaA’s decision to leverage the safety and supply infrastructure of Ogsiveo, already marketed for desmoid tumors in the FDA and EU, to pursue cost-effective follow-up studies.
Source: ClinicalTrials.gov (api_ct)