Rezatapopt Generates Rapid, Durable Responses Across Subgroups in Pretreated TP53 Y220C–Mutated Ovarian Cancer

Rezatapopt (PC14586), an investigational first-in-class, selective p53 reactivator, demonstrated clinically meaningful activity and a manageable safety profile in heavily pretreated patients with advanced ovarian cancer harboring a TP53 Y220C mutation, regardless of platinum status, prior therapies, or FRα expression, according to interim data from the phase 1/2 PYNNACLE trial (NCT04585750) presented during the 2026 Society of Gynecologic Oncology Annual Meeting.¹

The phase 2 monotherapy portion of the study is evaluating the efficacy and safety of rezatapopt in participants with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation. Among evaluable patients in the ovarian cancer cohort (n = 72), the overall response rate (ORR) per investigator assessment was 44.4% (95% CI, 32.7%-56.6%), comprising a complete response rate of 1.4% and a partial response (PR) rate of 43.1%. Stable disease (SD) was observed in 31.9% of patients, and progressive disease (PD) was observed in 6.9%; 16.7% of patients were not evaluable (NE).

Responses were rapid and durable, with a median time to response (TTR) of 1.3 months (95% CI, 1.3-1.5) and a median duration of response (DOR) of 8.2 months (95% CI, 4.2-12.9). Moreover, target lesion reduction was observed broadly across the ovarian cancer cohort, with deep tumor shrinkage observed in a substantial proportion of patients. At the March 29, 2026, data cutoff, approximately 40% patients with ovarian cancer remained on treatment.

"[Based on these data], rezatapopt offers a promising, orally administered, chemotherapy-free targeted monotherapy [option] for patients with ovarian cancer harboring a TP53 Y220C mutation,” Alison M. Schram, MD, lead investigator of the PYNNACLE trial, stated in a presentation of the data.

Schram is a gynecologic medical oncologist, early drug development specialist, and associate attending physician at Memorial Sloan Kettering Cancer Center in New York, New York.

What is the rationale for targeting TP53 Y220C in ovarian cancer?

The TP53 Y220C mutation is a key hotspot missense mutation present in approximately 1.1% of all solid tumors, approximately 3.1% of all ovarian cancers, and approximately 3.6% of high-grade serous ovarian cancers (HGSOC).¹

Rezatapopt is an investigational, first-in-class, selective p53 reactivator specific to the TP53 Y220C mutation.² The drug works by stabilizing the mutated p53 Y220C protein in the wild-type p53 conformation, thereby restoring p53 tumor suppressor function. Preclinical data have demonstrated restoration of p53 transcriptional activity and tumor regression in vivo with rezatapopt.

How was the PYNNACLE study designed?

PYNNACLE is a pivotal phase 2, global, multicohort basket trial assessing rezatapopt in patients with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation. The trial enrolled approximately 200 patients into 1 of 5 cohorts based on tumor type. Cohort 1 included patients with ovarian cancer and is the subject of this interim analysis. Additional cohorts enrolled patients with lung cancer (cohort 2), breast cancer (cohort 3), endometrial cancer (cohort 4), and all other solid tumors (cohort 5).¹

Eligible patients were adults 18 years or older or adolescents aged 12 to 17 years from Australia, South Korea, and the United States with locally advanced or metastatic solid tumors, excluding primary central nervous system tumors. Patients were required to have a documented TP53 Y220C mutation and KRAS wild-type status and to have received prior standard therapy or be ineligible for appropriate standard-of-care treatment.

Once enrolled, patients received rezatapopt at 2000 mg orally once daily with food.

The primary end point was ORR per blinded independent central review, evaluated both within the ovarian cancer cohort and across all cohorts. Key secondary end points included investigator-assessed ORR, TTR, DOR, disease control rate, progression-free survival per BICR and per investigator, overall survival, and safety.

What were the baseline characteristics of patients in the ovarian cancer cohort?

​​A total of 141 patients with solid tumors, including 76 patients with ovarian cancer (72 evaluable), were enrolled in PYNNACLE at the data cutoff. Baseline characteristics in this cohort were as follows:

• Median age: 66 years (range, 46-91)
• ECOG performance status: 0 (47%) or 1 (53%)
• Median prior lines of therapy: 4 (range, 1-10)
• Number of prior lines: 1 prior line (4%), 2 prior lines (18%), 3 prior lines (21%), ≥ 4 prior lines (57%)
• Prior bevacizumab (Avastin) exposure: 80% of patients
• Platinum status: platinum-sensitive (4%), platinum-resistant (61%), platinum-refractory (36%; includes 13% with primary platinum-refractory disease)
• Disease histology: high-grade serous (97.4%), clear cell (1.3%), sex cord stromal (1.3%)

Among 63 patients with available data on FRα expression, 48% were FRα positive, and 52% were FRα negative. BRCA mutation status was available for all 76 patients: 9% had a BRCA mutation, comprising somatic BRCA1/2 mutations (4%) and germline BRCA1/2 mutations (5%). Among 67 patients with available homologous recombination deficiency (HRD) data, 27 (40%) were HRD positive and 40 (60%) were HRD negative.

Were responses consistent across subgroups?

Clinically meaningful ORRs were observed across all prespecified subgroups of efficacy-evaluable patients in the ovarian cancer cohort. These response rates were as follows:

• Platinum-resistant patients (n = 44): ORR of 45.5% (95% CI, 30.4%-61.1%), with 20 PRs (45.5%), 16 SDs (36.4%), 2 PDs (4.5%), and 6 patients who were NE (13.6%)
• Platinum-refractory patients (n = 25): ORR of 44.0% (95% CI, 24.4%-65.1%), with 11 PRs (44.0%), 6 SDs (24.0%), 3 PDs (12.0%), and 5 patients who were NE (20.0%)
• Prior bevacizumab (n = 57): ORR of 43.9% (95% CI, 30.7%-57.6%), with 1 CR (1.8%), 24 PRs (42.1%), 18 SDs (31.6%), 5 PDs (8.8%), and 9 patients who were NE (15.8%)
• Prior PARP inhibitor (n = 38): ORR of 52.6% (95% CI, 35.8%-69.0%), with 1 CR (2.6%), 19 PRs (50.0%), 10 SDs (26.3%), 3 PDs (7.9%), and 5 patients who were NE (13.2%)
• FRα positive (n = 30): ORR of 50.0% (95% CI, 31.3%-68.7%), with 15 PRs (50.0%), 13 SDs (43.3%), 1 PD (3.3%), and 1 patient who was NE (3.3%)
• FRα negative (n = 31): ORR of 41.9% (95% CI, 24.5%-60.9%), with 13 PRs (41.9%), 7 SDs (22.6%), 3 PDs (9.7%), and 8 patients who were NE (25.8%)

What was the agent’s safety and pharmacokinetic profile?

Safety was evaluated in the full population of 141 patients. Treatment-related adverse effects (TRAEs) were predominantly grade 1 or 2, with no grade 5 TRAEs observed. The most frequent TRAEs were nausea (any grade, 41.8%; grade 1, 29.1%; grade 2, 12.8%; grade 3, 0%), fatigue (25.5%; 10.6%; 14.2%; 0.7%); and increased blood creatinine levels (22.0%; 7.1%; 13.5%; 1.4%).

Other TRAEs occurring in at least 10% of patients included as follows:

• Anemia (any-grade, 18.4%; grade 3, 5.7%; grade 4, 0.0%)
• Increased alanine aminotransferase levels (18.4%; 5.7%; 1.4%)
• Increased aspartate aminotransferase levels (18.4%; 5.7%; 0.7%)
• Vomiting (17.0%; 0.0%; 0.0%)
• Decreased appetite (12.8%; 0.0%; 0.0%)
• Diarrhea (11.3%; 0.0%; 0.0%)
• Pruritus (10.6%; 0.0%; 0.0%)

Laboratory abnormalities were generally manageable and monitorable, with most cases described as transient and reversible. A similar safety profile was observed specifically among patients with ovarian cancer (n = 76). Overall, 5.0% of patients across all cohorts discontinued treatment due to TRAEs, including 5.3% of those in the ovarian cancer cohort.

Pharmacodynamic data provided evidence of on-target rezatapopt activity in the ovarian cancer cohort. Among 55 patients with available circulating tumor DNA TP53 Y220C variant allele frequency (VAF) data at both baseline and at 3 to 6 weeks on treatment, 95% experienced a reduction in TP53 Y220C VAF. Of those patients, 85% had a reduction of at least 50%, and 60% had a reduction of at least 90%. Nearly all patients experiencing a radiographic response also showed a corresponding reduction in TP53 Y220C VAF, indicating rezatapopt’s on-target engagement of the mutant p53 Y220C protein.

Disclosures: Schram reported advisory board roles with Boehringer Ingelheim, Day One Biopharmaceuticals, Endeavor Biomedicines, Guardant, Mersana, Merus, Partner Therapeutics, PMV Pharma, Relay Therapeutics, Repare Therapeutics, Revolution Medicines, Schrödinger, and TransCode Therapeutics; advisory roles with Merus, Pfizer, PMV Pharmaceuticals Inc, Schrödinger, Repare Therapeutics, and Relay Therapeutics; and receipt of institutional research funding from ArQule, AstraZeneca, BeiGene/SpringWorks, Black Diamond Therapeutics, Boehringer Ingelheim, Debiopharm, Elevar Therapeutics, Elevation Oncology, Kura, Lilly, Merus, Northern Biologics, Partner Therapeutics, Pfizer, Pheon Therapeutics, PMV Pharmaceuticals, Relay, Repare Therapeutics, Revolution Medicines, and Surface Oncology.

References

1. Schram AM, Frenel J-S, Italiano A, et al. The 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: 2026 SGO Annual Meeting on Women's Cancer; April 10-13, 2026; San Juan, Puerto Rico.
2. Rezatapopt. PYNNACLE Clinical Study. PMV Pharmaceuticals, Inc. October 2025. Accessed April 12, 2026. https://www.pynnaclestudy.com/hcp/rezatapopt/