Clinical Summary: 

• Design/Context: The phase 2 PYNNACLE trial evaluated rezatapopt, a selective p53 reactivator, in patients with advanced ovarian cancer harboring TP53 Y220C mutations.
• Key Outcomes: Rezatapopt demonstrated consistent tumor shrinkage, durable responses, and manageable toxicity across a heavily pretreated population.
• Clinical Relevance: Targeting TP53 mutations represents a promising chemotherapy-free strategy in a molecularly defined subset of ovarian cancer, with ctDNA showing potential as a response biomarker.

Alison Schram, MD, Memorial Sloan Kettering Cancer Center, New York, New York, discusses results from the phase 2 PYNNACLE trial which assessed rezatapopt, a selective p53 reactivator, among patients with TP53 Y220C mutated advanced or metastatic ovarian cancer. 

Results demonstrated that rezatapopt showed meaningful response with durable activity and a favorable safety profile. 

Dr Schram presented these results at the 2026 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer in San Juan, Puerto Rico. 

Transcript: 

Hi, my name is Ali Schram, I’m from Memorial Sloan Kettering Cancer Center, and I’ll be discussing the results of the phase 2 PYNNACLE trial of rezatapopt, a selective p53 reactivator, in patients with advanced or metastatic solid tumors harboring TP53 Y220C mutations. This is the interim analysis from patients specifically with ovarian cancer.

As a way of background, the TP53 gene encoding the p53 protein is the most frequently mutated gene across cancers. This mutation destabilizes the p53 protein, causing a loss of the p53 tumor suppressor function. TP53 Y220C is a key hotspot missense mutation that’s present in about 1.1% of solid tumors and about 3.6% of patients with high-grade serous ovarian cancer.

Rezatapopt is an investigational first-in-class selective p53 reactivator that binds specifically to the p53 Y220C mutation. The mutated protein opens up a pocket that’s amenable to small-molecule binding by rezatapopt, and rezatapopt is able to stabilize the mutant protein in a wild-type conformation. This restores p53 function, leading to DNA binding and allowing p53 to carry out its transcriptional program.

We investigated rezatapopt in the PYNNACLE pivotal phase 2trial. This clinical trial enrolled patients who were aged 18 years or older and had locally advanced or metastatic solid tumors with a TP53 Y220C mutation identified on local testing. The overall clinical trial had 5 cohorts, and today I’ll be discussing the ovarian cancer cohort specifically. 

The end points were overall response rate per blinded independent central review, and key secondary end points included overall response rate per investigator, time to response, duration of response, disease control rate, progression-free survival, overall survival, and safety.

There were 76 patients enrolled with ovarian cancer as of the data cut. The median age was 66 years, with a range from 46 to 91. About half of patients had an ECOG performance status of 0, and about half had a performance status of 1. Patients were heavily pretreated, with a median of 4  prior lines of therapy, and 80% had prior bevacizumab. The vast majority were either platinum-resistant or platinum-refractory. If you look at biomarker status, folate receptor, BRCA, and HRD signatures, it was more or less what you would expect for an advanced ovarian cancer population. All but 2 patients had high-grade serous ovarian cancer, the other 2 had clear cell and sex cord stromal tumors.

Moving on to efficacy, there was deep tumor shrinkage observed in patients on rezatapopt treatment. The majority of patients had some degree of tumor shrinkage, and the overall response rate per RECIST was 44.4% in the overall cohort. If you break it down by subgroups, including platinum-resistant, platinum-refractory, prior bevacizumab, prior PARP inhibitor, and folate receptor-positive and -negative, you see that there are not meaningful differences between the groups, suggesting that the overall response rate is relatively consistent regardless of prior lines of therapy or biomarker status.

There was 1 complete response at the data cut, and subsequently 3 patients with partial responses went on to achieve complete responses after the data cut, suggesting continued evolution of the data.Patients had durable responses, the median time to response was 1.3 months, and the median duration of response was 8.2 months. About 40% of patients remained on treatment at the time of the data cut.

In terms of tolerability, rezatapopt treatment was very well tolerated overall. The most common treatment-related adverse events were nausea, fatigue, and increased blood creatinine. These events were mostly grade 1/2 and easily managed with supportive therapy. Only 5% of patients discontinued treatment due to a treatment-related adverse event.

If we look at the cell-free DNA data, we evaluated ctDNA at 3 to 6 weeks on treatment and compared it to baseline values. The vast majority of patients had a decline in their ctDNA Y220C variant allele frequency, 85% had a reduction greater than 50%, and 95% had a reduction overall. Looking at radiographic responses and how they correlate with ctDNA, there is a correlation. In patients who had a radiographic response, there were generally very significant declines in ctDNA as well.

We also looked at individual cases of interest. There was 1 patient highlighted who had additional TP53 mutations at baseline. She had heavily pretreated high-grade serous ovarian cancer and was treated with rezatapopt after 4 prior lines of therapy. Despite having other baseline TP53 mutations in addition to Y220C, she developed a durable complete response that was ongoing at 13.5 months.

In conclusion, in this interim analysis of the PYNNACLE phase 2 trial, single-agent rezatapopt showed clinically meaningful efficacy and a manageable safety profile in pretreated patients with TP53 Y220C–positive ovarian cancer. The overall response rate was 44.4%, the median duration of response was 8.2 months, and the discontinuation rate due to treatment-related adverse events was 5.3%.

Rezatapopt therefore offers a promising, orally administered, chemotherapy-free targeted monotherapy for patients with ovarian cancer harboring a TP53 Y220C mutation. I’d like to acknowledge, first and foremost, the patients and their caregivers, in addition to the study team and PMV, the sponsor of this trial.

Source: 

Schram A, Frenel JS, Italiano A, et al. The pivotal PYNNACLE phase 2 trial assessing rezatapopt, a selective p53 reactivator, in patients with advanced or metastatic solid tumors harboring a TP53 Y220C mutation: Interim analysis of patients with ovarian cancer. Presented at SGO Annual Meeting on Women’s Cancer. April 10 - 13, 2026; San Juan, Puerto Rico. Plenary 10.