PARP Inhibitor May Prolong Survival in Metastatic, BRCA-positive Breast Cancer

The PARP inhibitor talazoparib reduced the risk for disease progression or death by 46 percent compared with chemotherapy in patients with germline BRCA mutation—positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer, according to study results published in the New England Journal of Medicine.

In addition, patient-reported quality-of-life measures revealed a prolonged time to deterioration of overall health (24.3 months vs. 6.3 months).

“PARP inhibitors were directly compared to several standard chemotherapy regimens and were found to be better as far as disease control; but just as importantly, patients felt better when compared with chemotherapy,” study author Jennifer Litton, M.D., associate professor of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, said in an interview with CURE.

BRCA1/2 mutations — which account for 5 to 10 percent of breast cancers – cause defects in DNA damage repair of cells, and in this case, can be used to kill cancer cells. “Talazoparib works by stopping cancer cells from fixing themselves, and so the cancer cells die off instead of dividing and spreading,” Litton explained.

In the open-label, randomized, international phase 3 EMBRACA trial, the researchers compared the efficacy and safety of talazoparib or physician’s choice of treatment of single-agent chemotherapy in 431 women with locally advanced or metastatic and hereditary BRCA1/2 gene mutations.

Patients were randomized 2:1 to receive either 1 mg of talazoparib once daily (287 women) or standard therapy — either capecitabine, eribulin, gemcitabine or vinorelbine – in continuous 21-day cycles (144 women). Treatment continued until disease progression, unacceptable toxic effects, or withdrawal of consent occurred, or unless the physician decided to end treatment.

Progression-free survival (PFS) assessed by blinded independent central review served as the primary endpoint. Secondary endpoints included overall survival (OS), objective response rate (ORR), the clinical benefit rate at 24 weeks (complete response, partial response or stable disease), and the duration of response. Lastly, patient-reported outcomes were measured with the use of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and the breast cancer—specific QLQ-BR23.

Overall, 54 percent of participants had hormone-receptor (HR)-positive disease and 46 percent had triple-negative breast cancer, while 45 and 55 percent had BRCA1 and BRCA2 mutations, respectively.

The talazoparib arm demonstrated superior median PFS (8.6 months vs. 5.6 months) and ORR, or the percentage of patients with tumor shrinkage (62.6 percent vs. 27.2 percent) compared with the chemotherapy arm. Twelve women treated with talazoparib experienced a complete response.

Grade 3 to 4 hematological side effects occurred in 55 percent of patients treated with talazoparib compared with 39 percent of those given chemotherapy; however, the PARP inhibitor was associated with fewer high-grade non-hematological events.

Serious side effects occurred in 26 percent of the talazoparib arm and 25 percent of the chemotherapy group, and side effects resulting in death happened in 2.1 percent compared with 3.2 percent, respectively.

Final OS will be reported at a later date when the data fully matures, according to an MD Anderson-issued press release.

“If a patient has metastatic breast cancer and a known BRCA mutation, they should talk with their cancer care team to see if a PARP inhibitor may be an option for him or her,” Litton recommended.

The researchers plan to continue investigating the utility of PARP inhibitors in additional breast cancer patients with BRCA mutations, including those with early-stage disease, and the potential for enhancing its activity in patients without inherited BRCA mutations. “There are multiple ongoing studies looking at new combinations to see if more people can benefit, such as those without a BRCA mutation, or that the effects can be more long lasting,” Litton added.