Rezatapopt (p53 Y220C reactivator) drives 46% ORR in heavily pretreated TP53 Y220C ovarian cancer

Rezatapopt is an oral, first-in-class small-molecule “p53 reactivator” that selectively binds mutant TP53 Y220C, stabilizes p53 in a wild-type–like conformation, and aims to restore tumor-suppressor function. In the pivotal, single-arm PYNNACLE Phase 2 trial (NCT04585750), advanced ovarian cancer patients with TP53 Y220C (51 treated; efficacy-evaluable n=48) had investigator-assessed ORR 46% (95% CI 31–61), including 1 CR; ORR was 48% in platinum-resistant (n=27) and 44% in platinum-refractory (n=18), with median DoR 8.0 months (range 3.4–NR) and time to response 1.3 months. TRAEs (N=112 across solid tumors) were mostly Grade 1/2 (nausea 34%, fatigue 23%, creatinine increased 20%, ALT increased 18%), with discontinuations due to TRAEs in 4/112 (3.6%; ovarian n=1)—notably above typical single-agent chemo ORRs ~10–15% in platinum-resistant disease and even higher than mirvetuximab’s ~32% ORR in FRα-high PROC (but rezatapopt’s readout is investigator-assessed and biomarker-selected to ~3% of ovarian cancers).