Endometrial cancer is the most common gynecologic malignancy, yet incidence and mortality continue to rise. Advanced and recurrent disease carries a poor prognosis, and there are limited effective treatment options. Currently, patients may receive a single-agent therapy, but response rates are often less than 15% and new treatment strategies are needed.
Endometrial cancer is a heterogeneous disease with four molecular subtypes which creates complexity in finding effective treatments. The subtypes include POLE, DNA mismatch repair deficient (MMRd)/microsatellite instability high (MSI-H), copy-number high (CN-H)/p53-abnormal, and copy-number low (CN-L)/no specific molecular profile (NSMP). The categorization is prognostic cand the National Comprehensive Cancer Network recommends molecular subtype assessment for endometrial cancer patients.
CN-H/p53-abnormal endometrial cancers are characterized by recurrent TP53 mutations, high levels of copy number alterations, MMR-proficiency or microsatellite stability (MMRp/MSS), and lack pathogenic POLE mutations. The subtype typically includes high-grade histologic types, such as high-grade endometrioid carcinoma, serous carcinoma, and carcinosarcoma. This group is associated with the poorest prognosis of endometrial cancers.
Gynecologic medical oncologist at Memorial Sloan Kettering (MSK), Maria M. Rubinstein, MD treats patients with endometrial cancer and has been researching additional options for this hard-to-treat population. “In my practice, I’ve seen the need for better therapies to prolong survival and improve quality of life,” Dr. Rubinstein said. “We want to offer more to our patients in this aggressive and advanced cancer, but it is a complex disease.”
“Past research has shown some hope for advances in this area, and we felt this was an opportunity to improve treatment paradigms and patients’ lives,” Dr. Rubinstein said. The previous research has shown that CN-H/p53-abnormal endometrial cancer tumors molecularly may resemble high-grade serous ovarian cancer and basal-like breast cancer which also are characterized by TP53 mutations and often exhibit a homologous recombination deficiency (HRD) phenotype. In HRD diseases, poly (ADP-ribose) polymerase (PARP) inhibitors lead to DNA damage and cell death by blocking the repair of single-strand nicks or trapping PARP on the chromatin. HRD cells are without the mechanisms to repair the subsequent double-strand breaks through homologous recombination repair, and the cells are shunted to error-prone repair mechanisms which lead to progressive genomic instability, mitotic catastrophe, and ultimately cell death.
Dr. Rubinstein and colleagues were interested when seeing that preclinical models have shown that the combination of PARP inhibitors and immune checkpoint inhibitors have synergistic activity. Two recent Phase 3 studies also used PARP inhibitors in combination with immunotherapy. “There was a strong rationale to investigate the combination of PARP and immune checkpoint inhibition as a standalone regimen in the MMRp and CN-H/p53-abnormal subgroups,” she said.
Study Design and Findings
Dr. Rubinstein and colleagues conducted a Phase 2 study evaluating the efficacy and safety of PARP inhibitor olaparib (300 mg orally twice daily) plus immunotherapy pembrolizumab (200 mg IV every 3 weeks) in patients with persistent or recurrent CN-H/p53-abnormal endometrial cancer. Patients had POLE-negative disease and had undergone one to three prior lines of therapy. The single site, single-arm investigator-initiated open-label study had a primary endpoint of best overall response rate (ORR) at 24 weeks.
The study had 25 patients evaluable for efficacy. Of those, 2 patients achieved complete response and 6 achieved partial response. The ORR was 32%, and median duration of response was 11.2 months. Researchers found a median PFS of 3.9 months and median overall survival of 16.5 months. The genomic analyses suggested that responders had a numerically higher frequency of HRD tumors than nonresponders (50% vs. 17%). Researchers identified no new safety signals. Dr. Rubinstein concluded that this should be considered a potential treatment option for this population.
Learn more about MSK clinical trials for patients with endometrial cancer.