Dr Dumbrava on the Rationale for Evaluating Rezatapopt in TP53 Y220C–Mutated Ovarian Cancer

"All patients with ovarian cancer have a TP53 mutation, so developing drugs that are able to restore the normal TP53 wild type function is essential."

Ecaterina Dumbrava, MD, an associate professor in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, discussed the rationale and clinical development of rezatapopt (PC14586), a selective small molecule p53 reactivator being evaluated in the phase 2 PYNNACLE trial (NCT04585750) for patients with ovarian cancer and other solid tumors harboring TP53 Y220C mutations.

Dumbrava explained that most patients with high-grade serous ovarian cancer harbor TP53 mutations; however, effective therapies that restore wild-type p53 function remain lacking. The Y220C variant represents a structurally defined subset of TP53 mutations amenable to pharmacologic reactivation, and rezatapopt was designed to bind and stabilize the mutant p53 protein, thereby restoring its native conformation and reactivating tumor-suppressive functions.

The PYNNACLE trial, which builds upon preliminary findings from the phase 1 study of rezatapopt, is enrolling patients with locally advanced or metastatic solid tumors carrying the TP53 Y220C mutation, including those with ovarian and endometrial cancers where mutation prevalence is relatively higher. Dumbrava noted that early results from the phase 1 trial supported the biologic activity and tolerability of rezatapopt, prompting further evaluation in a larger, genomically defined cohort.

Patients enrolled in PYNNACLE must have confirmed TP53 Y220C-mutant tumors and meet eligibility criteria including adequate organ function and ECOG performance status. The study’s primary end point is objective response rate, with secondary end points including progression-free survival, duration of response, overall survival, and safety profile. The goal is to validate the role of selective p53 reactivation as a targeted therapeutic approach in tumors previously deemed undruggable due to the complexity of p53 inactivation.

Dumbrava emphasized that although the TP53 Y220C mutation represents a narrow molecular subset, the approach has broader implications for precision oncology and drug development strategies targeting tumor suppressor gene mutations. The trial’s focus on biomarker-driven patient selection, coupled with a mechanism-based therapeutic approach, reflects a paradigm shift toward individualized treatment strategies in oncology.

If successful, the findings from PYNNACLE could support the clinical utility of rezatapopt and encourage further efforts to expand targeted treatment options for patients with TP53-mutant cancers, Dumbrava concluded.