Rezatapopt Achieves Antitumor Activity Across Subgroups in TP53 Y220C–Positive Ovarian Cancer

Interim data from the phase 2 PYNNACLE trial (NCT04585750) shared at the 2026 SGO Annual Meeting showed that the novel agent rezatapopt (PC14586) was tolerable and elicited clinically meaningful antitumor activity in patients with heavily pretreated, TP53 Y220C mutation–positive advanced ovarian cancer.¹ The activity was observed regardless of platinum status, prior therapies, or FRαexpression.

Among evaluable patients in the ovarian cancer cohort (n = 72), the overall response rate (ORR) per investigator assessment with the first-in-class, selective p53 reactivator rezatapopt was 44.4% (95% CI, 32.7%-56.6%), comprising a complete response rate of 1.4% and partial response rate of 43.1%. Stable disease was observed in 31.9% of patients, progressive disease in 6.9%, and 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.

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).

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.

PYNNACLE Study Designed

PYNNACLE is a pivotal phase 2, global, multi-cohort basket trial assessing rezatapopt in patients with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation. The trial enrolled a basket of approximately 200 patients onto 1 of 5 cohorts according to 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).

Eligible patients were adults aged 18 years or older or adolescents aged 12 to 17 years in Australia, the Republic of 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 endpoint was ORR per blinded independent central review, evaluated both within the ovarian cancer cohort and across all cohorts. Key secondary endpoints included investigator-assessed ORR, TTR, DOR, disease control rate, PFS per BICR and per investigator, overall survival, and safety.

Baseline Characteristics in PYNNACLE Trial

​​A total of 141 patients with solid tumors, including 76 patients with ovarian cancer, 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% of patients) or 1 (53% of patients)
• 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.

Responses Were Consistent Across Subgroups

Clinically meaningful ORRs were observed across all pre-specified 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%)

Rezatapopt 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%), 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:

• 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 Relay Therapeutics, Mersana, Merus, Partner Therapeutics, PMV Pharma, Schrodinger, Repare Therapeutics, Revolution Medicine, Endeavor Biomedicines, Day One Biopharmaceuticals, Transcode Therapeutics, Guardant, and Boehringer Ingelheim; advisory roles with Merus, Pfizer, PMV Pharmaceuticals, Inc., Schrödinger, Repare Therapeutics, and Relay Therapeutics; and receipt of institutional research funding from AstraZeneca, ArQule, BeiGene/Springworks, Black Diamond Therapeutics, Boehringer Ingelheim, Debiopharm, Elevar Therapeutics, Elevation Oncology, Kura, Lilly, Merus, Northern Biologics, Partner Therapeutics, Pfizer, Pheon Therapeutics, PMV Pharma, Relay, Repare Therapeutics, Revolution Medicine, 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, PR.

2. Rezatapopt. PYNNACLE Clinical Study. PMV Pharmaceuticals, Inc. October 2025. Accessed April 12, 2026. https://www.pynnaclestudy.com/hcp/rezatapopt/