Single-agent rezatapopt produced “very deep and durable responses” in heavily pretreated patients with TP53 Y220C–mutated advanced ovarian cancer, according to updated results from the pivotal phase II PYNNACLE trial presented at the 2026 ASCO Breakthrough meeting in Singapore.

The analysis was presented by Tira J. Tan, BSc, MBBS, from the Division of Medical Oncology, National Cancer Centre Singapore. In the ovarian cancer cohort, the investigator-assessed objective response rate was 44.4%, with a median time to response of 1.3 months and a median duration of response of 8.2 months.

TP53 Y220C is a hotspot missense alteration that occurs in approximately 1.2% of all solid tumors, 3.2% of ovarian cancers, and approximately 3.7% of high-grade serous ovarian cancers.

— Tira J. Tan, BSc, MBBS

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Rezatapopt is an investigational, first-in-class, selective p53 reactivator designed for tumors harboring the TP53 Y220C mutation. It is not approved by the U.S. Food and Drug Administration, European Medicines Agency, or other regulatory authorities for the treatment of cancer, Dr. Tan noted. The agent binds to a mutation-induced pocket in Y220C-mutated p53, stabilizing the protein in a wild-type–like conformation and restoring tumor suppressor function.

“TP53 is the most frequently mutated gene across all cancers,” she said. “TP53 Y220C is a hotspot missense alteration that occurs in approximately 1.2% of all solid tumors, 3.2% of ovarian cancers, and approximately 3.7% of high-grade serous ovarian cancers.”

A Heavily Pretreated Ovarian Cancer Cohort

PYNNACLE is evaluating rezatapopt at 2,000 mg once daily with food in patients with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation. The ovarian cancer cohort is one of several tumor cohorts in the study. The primary endpoint is objective response rate by blinded independent central review, with key secondary endpoints including investigator-assessed objective response rate, time to response, duration of response, progression-free survival, overall survival, and safety.

At the updated cutoff, 141 patients had been enrolled across tumor types, including 76 patients in the ovarian cancer cohort. Patients in that cohort had a median age of 66 years, most had high-grade serous ovarian cancer, and the population was heavily pretreated, with a median of four prior lines of systemic therapy. Fifty-seven percent had received at least four prior lines, 80% had prior bevacizumab, 61% had platinum-resistant disease, and 36% had platinum-refractory disease. (See Keypoints.)

Among 72 efficacy-evaluable patients, the investigator-assessed objective response rate was 44.4%. Response rates were similar across subgroups, including 45.5% among patients with platinum-resistant disease, 44.0% among those with platinum-refractory disease, 43.9% among patients previously treated with bevacizumab, and 52.6% among those previously treated with a PARP inhibitor.

“These findings suggest that activity may be driven primarily by TP53 Y220C molecular dependency,” Dr. Tan said. “Taken together, these data support rezatapopt as a promising, orally administered, chemotherapy-free, targeted monotherapy for patients with ovarian cancers harboring the TP53 Y220C mutation.”

Safety and Molecular Response

The safety profile was generally manageable in the overall population of 141 patients and was similar in the ovarian cancer cohort. Treatment-related adverse events were mostly grade 1 or 2, the most common being nausea, fatigue, and increased blood creatinine. Laboratory abnormalities were described as generally manageable, transient, and reversible. No grade 5 treatment-related adverse events were reported.

Treatment discontinuation because of adverse events was infrequent. Seven of 141 patients overall discontinued treatment, including 4 of 76 patients in the ovarian cancer cohort, or about 5%.

Pharmacodynamic data also supported on-target activity. Among 55 patients with ovarian cancer who had paired baseline and on-treatment circulating tumor DNA samples available at 3 to 6 weeks, 52 patients, or 95%, had a reduction in the TP53 Y220C variant allele frequency, a blood-based measure of the mutation level; 85% had a reduction of at least 50%. Nearly all patients with a radiographic response also had a reduction in TP53 Y220C variant allele frequency.

Dr. Tan also presented a case example of a 64-year-old Asian woman with platinum-resistant high-grade serous ovarian cancer and four prior lines of therapy. After starting rezatapopt, the patient had an 82% reduction in target lesions by week 18 and a 100% reduction by week 50, consistent with a complete response. The response was ongoing beyond 12.3 months.

Discussant Perspective

Discussant Natalie Ngoi, MBBS, of the National University Cancer Institute, Singapore, placed the results in the broader context of recurrent ovarian cancer, particularly platinum-resistant disease, where effective options have historically been limited. She said rezatapopt could add another biomarker-selected option for this difficult-to-treat setting.

Dr. Ngoi highlighted the heavily pretreated nature of the ovarian cancer cohort, including the inclusion of patients with primary platinum-refractory disease.

Natalie Ngoi, MBBS

“I applaud the authors for enrolling primary platinum-refractory patients,” she said, noting that this group is often excluded from trials or underrepresented in clinical studies.

She emphasized the depth and durability of the efficacy signal. “The key take-home message for me is that we see very deep and durable responses,” she said.

She also highlighted the early molecular response data, particularly the reduction in TP53 Y220C variant allele frequency within the first 3 to 6 weeks of treatment. The presence of a defined molecular biomarker, she suggested, may make it possible to track response and resistance more reliably over time.

“When we think about the 40-year journey from the time of discovery of the TP53 protein to the time where it’s finally being effectively drugged in the clinic, I would really like to congratulate the authors,” Dr. Ngoi said. “I think that this represents a true breakthrough.”

Remaining Questions

Several questions remain, including where rezatapopt would fit among current and emerging options for platinum-resistant ovarian cancer. Dr. Ngoi pointed in particular to the growing role of biomarker-selected antibody-drug conjugates and other targeted strategies, including folate receptor alpha–directed therapies in eligible patients.

She also raised the possibility that the drug’s favorable tolerability profile could support exploration in earlier settings. “Could we see this used as maintenance therapy?” “Could we see this in the front-line setting for patients with TP53 Y220C–mutated tumors?”

Dr. Ngoi emphasized the need to better understand predictors of response beyond the presence of TP53 Y220C and to study mechanisms of resistance. Longitudinal circulating tumor DNA monitoring, she suggested, may help clarify which patients are most likely to benefit and how resistance emerges over time.

Dr. Tan said the study continues to enroll patients with ovarian or endometrial cancers harboring TP53 Y220C. 

DISCLOSURE: Dr. Tan reported honoraria from AstraZeneca, Gilead Sciences, and Pfizer; consulting or advisory roles with AstraZeneca, Daiichi Sankyo/AstraZeneca, DKSH, Gencurix, Gilead Sciences, Menarini, and MSD Oncology; speakers’ bureau participation for Daiichi Sankyo/AstraZeneca and MSD Oncology; institutional research funding from AstraZeneca, Bayer, Daiichi Sankyo/AstraZeneca, Iksuda Therapeutics, Lilly, MSD Oncology, Novartis, PMV Pharma, Roche/Genentech, and Sanofi; research funding from Atavistik Bio and Prelude Therapeutics; and travel, accommodations, and expenses from Daiichi Sankyo Singapore, MSD, MSD China, and Roche. Dr. Ngoi reported honoraria from AbbVie (institutional), AstraZeneca, Bristol-Myers Squibb/Medarex, GlaxoSmithKline (institutional), MSD Oncology, and Pfizer; consulting or advisory roles with Bristol-Myers Squibb/Medarex, MSD Oncology, and Pfizer; speakers’ bureau participation for MSD Oncology; research funding from iOnctura; and travel, accommodations, and expenses from AstraZeneca and MSD Oncology.

REFERENCE

1. Tan TJ, Dumbrava EE, et al: Pivotal PYNNACLE phase II trial of rezatapopt in heavily pretreated, advanced solid tumors with a TP53 Y220C mutation. 2026 ASCO Breakthrough Meeting. Abstract 201. Presented June 26, 2026.