A phase II trial of pembrolizumab plus olaparib for the treatment of patients with persistent/recurrent endometrial cancers.

5597 Background: Copy number-high (CNH) ECs are characterized by high levels of copy-number alterations and TP53 mutations, and a subset may have a homologous recombination-deficiency (HRD) phenotype. The presence of an HRD-phenotype within CNH EC provides the rationale for using OLA in combination with PEM, as this exploits the mechanism of immune priming which creates further genomic instability and drives immune response. Methods: This is an investigator-initiated, single- arm, open-label, phase II trial evaluating the efficacy and safety of PEM + OLA in pts with persistent/recurrent TP53 -mutant EC. Key eligibility criteria included age ≥18 years, measurable disease, £3 prior lines of therapy, all histologic types allowed with aberrant p53 IHC and/or mutant TP53 . Carcinosarcomas were eligible if the epithelial component met the p53/ TP53 criteria. dMMR/MSI-H and POLE hotspot tumors were not eligible. All were PEM and OLA naïve and received OLA orally at 300mg every 12 hours and PEM 200mg every 3 weeks IV. Primary endpoint was objective response rate (ORR) by 24 weeks per RECIST 1.1. Results: At data cut off (December 12, 2024), 26 patients (pts) initiated therapy and 25 pts were evaluable for efficacy. Median age was 68 years (range:59-83). 13 pts (50%) had serous, 8 pts (31%) were mixed/high grade, and 4 pts (15%) had carcinosarcoma histology. 24 pts (92%) had 1 line of prior chemotherapy. 1 pt had a germline BRCA2 and 1 pt had a somatic BRCA1 mutation. 2 pts achieved complete response (CR), 6 pts achieved partial response (PR), resulting in an ORR of 32% (90% one-sided CI: 19.6-100%). Median duration of response was 10.5 months (80% CI:6.4-11.8). Median progression-free survival (PFS) was 4.8 months (80% CI: 3.6-5.9), and median overall survival (OS) was 21.2 months (80% CI: 9.4-NE). 50% (2/4) of carcinosarcoma pts achieved CR and PR, respectively. Most common ≥ grade 3 treatment related adverse events were anemia (12%), neutropenia (19%). 1 pt developed grade 3 pneumonitis, 2 pts developed grade 2 adrenal insufficiency. No new safety signals were identified. Conclusions: The combination of PEM + OLA has promising activity with durable responses observed in pts with persistent/recurrent TP53 -mutant EC, including carcinosarcomas. Molecular subtype selection is critical in further investigation of this combination. Clinical trial information: NCT05156268 .