Pivotal PYNNACLE phase 2 trial of rezatapopt in heavily pre-treated, advanced solid tumors with a <i>TP53</i> Y220C mutation: Initial ovarian cancer analysis.

Abstract

201 Background: TP53 Y220C mutations occur in ~3% of ovarian cancers. Rezatapopt, an investigational, first-in-class, p53 reactivator, selectively binds to Y220C-mutated p53, stabilizing it in wildtype conformation and restoring p53 function. Methods: PYNNACLE (NCT04585750) is a pivotal, single-arm phase 2 trial of rezatapopt (2000 mg once daily) in locally advanced or metastatic solid tumors with a TP53 Y220C mutation. Primary endpoint: Overall response rate (ORR; blinded independent central review; RECIST v1.1) across tumor cohorts and in the ovarian cancer cohort. Key secondary endpoints: Investigator-assessed ORR, other efficacy endpoints, safety. Efficacy evaluable: Patients (pts) with first post-baseline tumor assessment or discontinued early. Initial analysis in ovarian cancer is shown. Results: By 4 Sep 2025, of 112 pts receiving rezatapopt, 51 had ovarian cancer. Median age was 67 years (range 46–91), ECOG score was 0 (48%) or 1 (52%), and 49 (96%) pts had high-grade serous ovarian cancer. At study entry, 30 (59%) pts were platinum resistant, 18 (35%) were platinum refractory (primary platinum refractory n=7), and 3 (6%) were platinum sensitive. Pts were heavily pre-treated (median prior lines 4; range 1–10); 40 (78%) had prior bevacizumab. Investigator-assessed ORR (Table) was 46% in efficacy-evaluable pts, 48% in platinum-resistant pts, 44% in platinum-refractory pts, and 46% in pts who had prior bevacizumab. Median time to response and duration of response were 1.3 (range 1.2–1.4) and 8.0 months (range 3.4–not reached), respectively. Treatment-related adverse events (TRAEs) in all pts (N=112) were mostly Grade 1/2; most frequent (&gt;15%): nausea (34%), fatigue (23%), blood creatinine increase (20%), alanine aminotransferase increase (18%). Four pts (ovarian cancer n=1) discontinued due to TRAEs. Conclusions: In this initial analysis of the pivotal PYNNACLE Phase 2 trial, rezatapopt showed clinically meaningful efficacy and manageable safety in heavily pre-treated pts with TP53 Y220C-positive advanced ovarian cancer. Rezatapopt offers promising targeted therapy for ovarian cancer with a TP53 Y220C mutation. Clinical trial information: NCT04585750 . Efficacy evaluable patients All ovarian cancern=48 Platinum resistantn=27 Platinum refractory a n=18 Prior bevacizumabn=37 Prior PARP inhibitor n=29 Folate receptor alpha (FRα) positive b n=21 FRα negative b n=20 Overall response rate, c %(95% CI) 46(31–61) 48(29–68) 44(22–69) 46(30–63) 52(33–71) 48(26–70) 40(19–64) Best response, n Complete response 1 0 0 1 1 0 0 Partial response 18 12 6 14 13 9 6 Unconfirmed partial response d 3 1 2 2 1 1 2 Stable disease 14 8 5 10 7 9 4 Progressive disease 4 2 2 4 2 1 2 Not evaluable 8 4 3 6 5 1 6 a Relapse during or within 1 month of platinum therapy; b FRα expression ≥75% (positive) or &lt;75% (negative) of viable tumor cells; c Complete + partial response (confirmed + unconfirmed); d Pending confirmation.