PARP Inhibitors May Have Benefit in BRCA-Mutant Endometrial Cancers

Julia Fehniger, MD

Tumors from a significant percentage of patients with endometrial cancer at NYU Langone Health’s Perlmutter Cancer Center were found to have BRCA1/2 somatic mutations, according to findings presented at the 2020 SGO Winter Meeting.¹ These data suggest that these cancers can be treated with PARP inhibitors, which have demonstrated efficacy in other BRCA1/2-mutant tumors.

Julia Fehniger, MD, a third-year oncology fellow at NYU Langone Health’s Perlmutter Cancer Center, presented findings from a study characterizing the prevalence of somatic mutations among women treated for advanced or recurrent endometrial cancer at the institution from January 2013 to July 2019 (n = 89). Investigators recorded genomic alterations including microsatellite instability (MSI) and tumor mutational burden (TMB), extracted clinicopathologic and treatment data from electronic medical records, and compiled descriptive statistics of patients both with and without somatic BRCA1/2 mutations.

Thirteen (15%; 95% CI, 8-24) women had somatic mutations while the majority of patients (n = 76; 85%) did not. Of the women with BRCA 1/2 mutations, 9 (69%) were white and 4 (31%) were black or non-Hispanic.

In the overall cohort, 50 patients were white (56%), 4 (5%) were Hispanic, 24 (27%) were black or non-Hispanic, and 11 (12%) of patients were Asian.

In the BRCA1/2-mutant cohort, 5 (38%) of patients had grade 1/2 endometrioid tumors; 4 (31%) had grade 3 endometrioid tumors (31%) and 2 (15%) had carcinosarcoma. One (8%) patient had dedifferentiated tumors and 1 (8%) had serous disease. Serous histology was the most common in the overall cohort (30%; n = 27).

Women with stage IIIA/B disease made up 12% of the total cohort, but represented 54% of those with BRCA1/2 somatic mutations. Overall, 67 (75%) women in the total cohort had recurrent disease, 6 (46%) of whom had BRCA1/2 somatic mutations.

Five patients had mutations in BRCA1, 9 had mutations in BRCA2, and 1 patient had mutation in both. Six patients underwent germline genetic testing. Of those, 4 were positive for germline BRCA mutation, 2 each in BRCA1 and BRCA2. Only 1 patient with a germline BRCA1/2 mutation had a tumor that was microsatellite instability-high (MSI-H) or high-TMB.

Eight (62%) mutations were classified as frameshift, 3 (23%) were nonsense, and 1 (8%) each was missense or splice site. Seven patients had MSI-H tumors and 9 had high-TMB. Fehniger said this finding suggests that a portion of these mutations are passengers.

“We don't have loss of heterozygosity or homologous recombination deficiency data for this patient population, but investigation of both of these assays in these tumors may provide a rationale for the activity of PARP inhibitors in this subset of patients with endometrial cancer,” she said.

Additionally, preclinical studies have shown that patients who have a PTEN deficiency may respond to PARP inhibitors.² More than 80% of patients with endometrial cancers have a PTEN mutation.

There are a handful of ongoing trials exploring PARP inhibitors in endometrial cancer. Investigators are currently recruiting for a phase I/IIa study (NCT03572478) of the combination of nivolumab (Opdivo) in combination with the PARP inhibitor rucaparib (Rubraca) for patients metastatic/recurrent endometrial cancer, as well as those with metastatic castration-resistant prostate cancer.

The phase I portion of the trial will establish the maximum-tolerated dose (MTD). In the phase II part, patients will be randomized to rucaparib alone, nivolumab alone, or the combination of the 2 drugs.

Investigators are also recruiting for the prospective, multicenter, phase II DOMEC trial (NCT03951415). Patients with recurrent, refractory, or metastatic endometrial cancer or carcinosarcoma of the uterus will be assigned to 300 mg of twice-daily oral olaparib (Lynparza) plus 1500 mg of intravenous durvalumab (Imfinzi) every 4 weeks. The primary endpoint is progression-free survival.

Moreover, in a phase Ib trial (NCT03586661), investigators are recruiting patients with recurrent endometrial, ovarian, primary peritoneal, or fallopian tube cancer. In the study, patients will be treated with the combination of niraparib (Zejula) and copanlisib (Aliqopa) and investigators will establish MTD and the recommended phase II dose.

References

1. Fehniger J, Levine DA, Pothuri B. BRCA1/2 somatic mutations in patients with advanced or recurrent endometrial cancer. Presented at: SGO 25th Annual Winter Meeting; February 6-8; 2020; Snowmass, CO.
2. Dedes KJ, Wetterskog D, Mendes-Pereira AM, et al. PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors. Sci Transl Med. 2010;2(53):53ra75. doi: 10.1126/scitranslmed.3001538.

<<< View more from the 2020 SGO Winter Meeting