Excitement Grows About PARP Inhibitors in BRCA-Mutated TNBC

Christina Loguidice
Published: Wednesday, Apr 04, 2018
Joyce A. O’Shaughnessy, MD
Joyce A. O’Shaughnessy, MD
Approximately 15% to 20% of breast cancers are of the triple-negative phenotype, testing negative for estrogen receptors (ERs), progesterone receptors, and HER2.1 Historically, triple-negative breast cancer (TNBC) tumors have been associated with an aggressive and early pattern of metastases and a lack of therapeutic targets compared with endocrine-sensitive tumors. TNBC tumors include many subgroups with distinct molecular characteristics and biomarkers, paving the way for improved targeted treatments in the near future. With the recent FDA approval of the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib, patients with TNBC and deleterious germline BRCA mutations now have a targeted treatment.2 During an OncLive Peer Exchange® moderated by Joyce A. O’Shaughnessy, MD, a panel of experts discussed the role of BRCA1/2 mutation testing and how and when to incorporate PARP inhibitors into the care of patients with BRCA-positive TNBC. They also discussed the potential for combining PARP inhibitors with other agents.

Expanded Role of BRCA1/2 Testing

A strong association has been shown between TNBC and BRCA mutations, particularly with respect to the BRCA1 gene. The proportion of BRCA1 mutations among triple-negative cases has been reported to range from 7% to 28%, whereas the proportion of BRCA2 mutations ranges from 1% to 17%.3 In patients with TNBC, the National Comprehensive Cancer Network (NCCN) recommends genetic risk evaluation in those diagnosed at ≤60 years.3 With the approval of olaparib, the NCCN expanded its BRCA1/2 testing recommendations to include patients with recurrent or metastatic HER2-negative disease eligible for single-agent therapy.4

“We no longer have to restrict [BRCA1/2 testing] to the early stage, as it now makes sense in the metastatic HER2-negative setting because we have a novel therapeutic available,“ said O’Shaughnessy. The other panelists concurred. “I think it’s very reasonable to test anyone with metastatic TNBC for BRCA,” said Aditya Bardia, MD, MPH. “Even if I identify [only a handful of] patients who otherwise would not have been identified based on the classic family history associated with BRCA carriers, I would be happy.”

However, to ensure proper identification of such patients, clinicians might need to readdress genetic counseling conversations. “There’s a pool of patients to whom we may have mentioned genetic counseling who didn’t pursue that, and now this has treatment implications and is not just risk assessment,“ said Tiffany Traina, MD. “We need to make sure we’re not missing potential candidates for [PARP inhibitor] therapy.”

PARP Inhibitor Therapy for TNBC

In January 2018, olaparib (Lynparza) became the first FDA-approved treatment for patients with germline BRCA-mutated, HER2-negative metastatic breast cancer.2 It is indicated for those previously treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Approval was based on data from the OlympiAD study (NCT02000622), which randomly assigned patients 2:1 to olaparib 300 mg orally twice daily or physician’s choice of chemotherapy (capecitabine, vinorelbine, or eribulin).5 “There was a significant improvement in progression-free survival [PFS] on the order of about 3 months [7.0 months for olaparib versus 4.2 months for chemotherapy],“ said Claudine Isaacs, MD, noting the objective response rate (ORR) was about 60%.

Another PARP inhibitor that is expected to be approved soon for patients with germline BRCA1/2 mutations is talazoparib (BMN 673), which is being assessed in the EMBRACA trial (NCT01945775).6 “Again, there was about a 3-month prolongation in PFS, so very similar findings favoring the use of a very targeted therapy in this group of patients,“ said Isaacs. In the study, the median PFS was 8.6 months for those receiving talazoparib and 5.6 months for those receiving physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). The ORR was 62.6%, which is comparable to that observed with olaparib in OlympiAD.

View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: 16th Annual International Congress on the Future of Breast Cancer®Sep 29, 20182.0
School of Breast Oncology®: Mid-Year Video Update OnlineSep 30, 20182.0
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