Abstract Purpose: 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 recombination deficient (HRD), potentially conferring sensitivity to PARP inhibitors. We aimed to test the combination PARP and immune checkpoint inhibitors in this subgroup, leveraging possible synergy from immune priming. Patients and Methods: We conducted a single-arm, open-label, phase II trial evaluating the efficacy and safety of olaparib (300 mg orally twice daily) plus pembrolizumab (200 mg IV every 3 weeks) in patients with persistent or recurrent CN-H/p53-abnormal endometrial cancer. Eligible patients had p53-abnormal, MMRp, and POLE-negative disease, and up to 3 prior lines of therapy. The primary endpoint was best overall response rate (ORR) at 24 weeks. Results: Of the 25 patients evaluable for efficacy, 2 patients achieved complete response, and 6 achieved partial response, resulting in an ORR of 32% (90% one-sided confidence interval CI: 19.6-100%). Median duration of response was 11.2 months (80% two-sided CI: 6.4-11.9). Median progression-free survival was 3.9 months (80% two-sided CI: 2.1-5.8), and median overall survival was 16.5 months (80% two-sided CI: 9.6-23.6). No new safety signals were identified. Genomic analyses suggested that responders had a numerically higher frequency of HRD tumors than non-responders (50% vs. 17%). Conclusions: The combination of olaparib plus pembrolizumab has promising activity with durable responses in patients with persistent or recurrent CN-H/p53-abnormal endometrial cancer. Molecular biomarkers may be helpful for patient selection in future studies of this combination.
Rubinstein et al. (Wed,) studied this question.