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The Desmoid Tumor Research Foundation

May 2024

Onset and resolution of ovarian toxicity with nirogacestat treatment in females with desmoid tumors: Updated safety analyses from the DeFi phase 3 study

Author Information

Elizabeth T Loggers 1, Rashmi Chugh 2, Noah Federman 3, Lee Hartner 4, Richard F Riedel 5, Sunny Cho 6, David Hyslop 6, Allison Lim 6, Ana B Oton 6, Kutluk H Oktay 7

1Clinical Research Division, Fred Hutchinson Cancer Center/Division of Hematology and Oncology, University of Washington, Seattle, Washington, USA. 2University of Michigan, Rogel Comprehensive Cancer Center, Ann Arbor, Michigan, USA. 3Departments of Pediatrics and Orthopaedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, California, USA. 4University of Pennsylvania, Abramson Cancer Center, Pennsylvania Hospital, Philadelphia, Pennsylvania, USA. 5Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA. 6SpringWorks Therapeutics, Inc, Stamford, Connecticut, USA. 7Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA.

Publication

Cancer

Summary

Introduction: Nirogacestat is a targeted gamma secretase inhibitor approved in the United States for adults with progressing desmoid tumors. In the phase 3 DeFi study (NCT03785964) of nirogacestat, ovarian toxicity (OT) was identified as a safety signal among females of reproductive potential (FORP). This analysis further describes the incidence, presentation, and resolution of OT. Methods: Patients were randomized to twice-daily oral nirogacestat (150 mg) or placebo, taken in continuous 28-day cycles. Investigator-identified OT in FORP was based on abnormal reproductive hormone values or perimenopausal symptoms (or both). Adverse event follow-up was conducted to assess OT resolution. Post hoc analyses included return of menstruation and return of follicle-stimulating hormone (FSH) to within normal limits (WNL) (≤20.4 mIU/mL). Results: Of 92 randomized females, 73 in the safety population were FORP (n = 36 nirogacestat, n = 37 placebo). OT was identified in 75% (27 of 36) receiving nirogacestat and 0% (0 of 37) receiving placebo. As of October 24, 2022, investigators reported OT resolution in 78% (21 of 27) of patients, with median OT duration of 19.1 weeks. Off-treatment resolution was reported in all 11 patients (100%) who stopped nirogacestat treatment; of these, all nine with available menstruation information experienced return of menstruation and eight had FSH WNL at last reported assessment. Resolution was reported in 10 of 14 (71%) while on nirogacestat; of these, all 10 experienced return of menstruation and seven had FSH WNL. Two patients were lost to follow-up. Conclusion: Most FORP treated with nirogacestat experienced OT, with the majority resolving, including all who stopped treatment, suggesting that OT is transient.

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