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

• Published in: Cancer Vol. 130; no. 16; pp. 2812 - 2821
• Main Authors: Loggers, Elizabeth T., Chugh, Rashmi, Federman, Noah, Hartner, Lee, Riedel, Richard F., Cho, Sunny, Hyslop, David, Lim, Allison, Oton, Ana B., Oktay, Kutluk H.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 15.08.2024
• Subjects: Females; fertility; Follicle-stimulating hormone; gamma secretase; GSI; Menstruation; oncology; ovarian dysfunction; Ovaries; Placebos; Receiving; Safety; Secretase; Toxicity; Tumors; women of childbearing potential; women of childbearing potential; GSI; gamma secretase; oncology; fertility; ovarian dysfunction
• ISSN: 0008-543X; 1097-0142; 1097-0142
• DOI: 10.1002/cncr.35324

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. In the phase 3 DeFi study of nirogacestat, a targeted gamma secretase inhibitor approved in the United States for adults with progressing desmoid tumors, ovarian toxicity was identified as a safety signal in most females of reproductive potential. The majority (78%) of ovarian toxicity events resolved, including in 100% of patients who stopped nirogacestat for any reason, suggesting that ovarian toxicity with nirogacestat is transient.