Summary

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• This summary is based on the review of two randomized controlled trial(s). ^[1-2]
• Nirogacestat significantly improved progression-free survival (PFS) in a phase 3 trial, demonstrating a hazard ratio of 0.29, with a 95% confidence interval (CI) of 0.15 to 0.55 (P < 0.001) compared to placebo. At 2 years, the probability of being event-free was 76% in the nirogacestat group versus 44% in the placebo group.
• Objective Response Rate (ORR): The ORR was higher in the nirogacestat group (41%) compared to placebo (8%; P<0.001), with a shorter median time to response in the nirogacestat group (5.6 months vs. 11.1 months for placebo).
• Complete Response (CR) and Secondary Outcomes: Complete response occurred in 7% of nirogacestat patients compared to 0% in the placebo group. Significant improvements were also observed in secondary outcomes, including patient-reported pain, symptom burden, and health-related quality of life (P ≤ 0.01).
• Ovarian toxicity (OT) occurred in 75% (27 of 36) of females of reproductive potential (FORP) in the nirogacestat group, with no cases observed in the placebo group. OT resolved in 78% (21 of 27) of cases, with a median resolution time of 19.1 weeks. Off-treatment resolution was noted in all 11 patients who discontinued nirogacestat.
• The most frequent adverse events associated with nirogacestat included diarrhea (84%), nausea (54%), fatigue (51%), hypophosphatemia (42%), and maculopapular rash (32%), with 95% of these events being grade 1 or 2 in severity.
• In the nirogacestat trial, FORP were a key population, with 75% (27 of 36) experiencing OT. The majority (78%) of OT cases resolved, with a median duration of 19.1 weeks, and all patients who stopped treatment experienced full resolution. There were consistent improvements in progression-free survival across all prespecified subgroups, though specific details were not provided.