A Phase II Trial of Olaparib plus Pembrolizumab in Patients with Recurrent Copy Number-High/p53-Abnormal Endometrial Cancer.

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.