Phase 2 trial of olaparib plus pembrolizumab for recurrent copy number-high/p53-abnormal endometrial cancer

Copy number-high (CN-H)/p53-abnormal endometrial cancers are high-grade uterine malignancies characterized by TP53 mutations, copy-number alterations, mismatch repair proficiency (MMRp), and absence of POLE mutations. A subset may be homologous recombinant deficient (HRD), potentially conferring sensitivity to PARP inhibitors. A phase 2 trial at Memorial Sloan Kettering Cancer Center (New York, NY) evaluated the combination of a PARP inhibitor and an immune checkpoint inhibitor in this subgroup. The trial included patients with persistent or recurrent p53-abnormal, MMRp, POLE-negative disease and up to 3 prior lines of therapy. The patients received olaparib 300 mg orally twice daily plus pembrolizuamb 200 mg intravenously every three weeks. The primary endpoint was best overall response rate (ORR) at 24 weeks. Of 25 efficacy evaluable patients, two achieved a complete response and six a partial response, for and ORR of 32% (90% CI 19.6-100). The median duration of response was 11.2 months (80% CI 6.4-11.9), the median progression-free survival was 3.9 months (2.1-5.8), and the median overall survival was 16.5 months (9.6-23.6). No new safety signals were identified. Responders had a numerically higher frequency of HRD tumors than nonresponders (50% versus 17%). The authors conclude that the combination of olaparib and pembrolizumab had promising activity with durable responses in patients with persistent or recurrent CN-H/p53-abnormal endometrial cancer.