Caitlin Kaczynski

Clinical characteristics and prior treatments of study participants.

Exploratory analysis of the three components of the HRD score.

Comparison of HRD scores in primary vs. recurrent disease and untreated vs. previously treated disease.

Representativeness of study participants.

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 poly (ADP-ribose) polymerase (PARP) inhibitors. We aimed to test the combination of 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 intravenously 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 the best overall response rate (ORR) at 24 weeks. Results: Of the 25 patients evaluable for efficacy, 2 patients achieved a complete response, and 6 achieved a partial response, resulting in an ORR of 32% [90% one-sided confidence interval (CI), 19.6%–100%]. The median duration of response was 11.2 months (80% two-sided CI, 6.4–11.9). The median progression-free survival was 3.9 months (80% two-sided CI, 2.1–5.8), and the 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 nonresponders (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.