Monitoring ovarian function in oncology studies: Results and insights from the DeFi phase 3 study of nirogacestat in desmoid tumor.
Authors: Loggers Elizabeth Trice , Chugh Rashmi , Hartner Lee P. , Riedel Richard F. , Cho Sunny , Hyslop David , Lim Allison , Oton Ana B. , Federman Noah 
Published: June 2024

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Background: Initiated in 2019, DeFi (NCT03785964) was a phase 3 study that incorporated comprehensive assessment of ovarian function prior to the 2023 ASCO guidance (Cui et al. Lancet Oncol) on assessing ovarian toxicity (OT) in oncology clinical trials. In DeFi, OT was identified as a safety signal with nirogacestat (niro), a selective gamma secretase inhibitor FDA-approved for adults with progressing desmoid tumors. We provide results and insights in assessing OT in females of reproductive potential (FORP) from DeFi. Methods: Patients were randomized to twice-daily oral niro or placebo (pbo). Investigator-identified OT and resolution in FORP were based on abnormal reproductive hormone values (increased follicle-stimulating hormone [FSH] or luteinizing hormone; decreased progesterone, anti-Müllerian hormone [AMH], or estradiol) assessed via scheduled testing, perimenopausal symptoms, or both. Based on the ASCO guidance, patient-level post hoc analyses included return of menses and last-reported FSH levels to within normal limits (WNL; ≤20.4 mIU/mL). Results: In the DeFi safety population, 73 were FORP (niro = 36, pbo = 37). Investigators identified OT in 0% of FORP receiving pbo and 75% (27/36) receiving niro. As of Oct2022, investigators reported that OT resolved in 78% (21/27): 100% (11/11) after stopping niro treatment for any reason (4 discontinued niro due to OT) and 71% (10/14) while remaining on niro; 2 were lost to follow-up. Of the 11 patients with off-treatment resolution, all met at least one of the recommended ASCO criteria for assessing OT resolution; all 9 with available menstruation information experienced return of menses and 8 had FSH WNL. Insights: Study limitations included timing of hormonal assessments (scheduled to study visits and not menstrual cycle), lack of menstrual diaries, and incomplete hormone assessments for some patients. Capture of OT can pose challenges, as MedDRA coding may not reflect adverse events observed in the female reproductive system. Further, hormone levels during DeFi could have been impacted by baseline ovarian function and prior use of gonadotoxic drugs/multiple lines of therapy. Hormone measures in clinical studies are important to determine a drug’s effects on ovarian function. However, there is presently no scientific consensus for hormone monitoring during cancer therapy or niro treatment in clinical practice. Ultimately, it is important to understand the patient’s fertility goals and to monitor ovarian function during oncology clinical trials. Conclusions: In DeFi, 75% of FORP treated with niro experienced OT. Most events resolved, including in 100% who stopped treatment for any reason, suggesting OT with niro is transient. Though initiated prior to the ASCO guidance, OT assessments in DeFi generally align with and support the use of both clinical measures and hormone biomarkers in oncology clinical trials. Clinical trial information: NCT03785964 .