Case 4: Looking Forward in BRCA+ Metastatic TNBC

Tiffany Traina, MD: The importance of germline genetic testing has really never been greater than of late where this has become not only important for, say, personal risk assessment and family risk, but it is now an actionable alteration that we have drugs with therapeutic benefit as a result of knowledge of somebody’s germline BRCA status.

In women who have even an early stage diagnosis of triple-negative breast cancer under the age of 60, we’re recommending germline genetic testing.

And in the setting of metastatic disease, when tumors are HER2 negative, that is absolutely an indication to undergo germline genetic testing for the exact purpose of identifying those with BRCA1 or BRCA2 mutations that could allow them to have a more optimal treatment approach as a result of that mutation.

Patients with triple-negative breast cancer and germline BRCA mutations have been shown to have an advantage to a platinum over a taxane in the first-line setting, based on the TNT data from Andy Tutt MBChB, PhD, that has now been published and presented some time ago.

In the subset of patients with germline mutations, the benefit to carboplatin, in that study, was superior to that of docetaxel. I will say that, in my practice, if I am treating a woman with a germline BRCA mutation I am now probably more likely to utilize a PARP inhibitor than a platinum, based on some of the data that have been presented from the OlympiAD study and from the EMBRACA trials.

The recent FDA approval of PARP inhibitors has been a wonderful treatment opportunity for our patients with germline BRCA1 or BRCA2 breast cancer and advanced disease.

The OlympiAD study that has been published now a couple of years ago, was a large phase 3 trial randomizing women with germline BRCA mutations to either single-agent olaparib or treatment of physician’s choice, which included several very typical standard-of-care chemotherapy options for our patients with advanced disease.

And what that trial showed was a significant improvement in progression-free survival for patients receiving the PARP inhibitor over that of chemotherapy.

I thought what was also wonderful for our patients is to see that the PARP, as a single agent, was well tolerated. Time to benefit was comparable to that of chemotherapy. The decline in health-related quality of life metrics was lower, if you will, with the PARP inhibitor over chemotherapy, And so I think both based on the efficacy advantage to the PARP inhibitor, as well as the better toxicity profile, being able to utilize a simple single-agent oral regimen, such as the PARP inhibitor, was favored for these patients.

Subsequent to the OlympiAD study, the EMBRACA trial reported out, which was quite similar, investigating talazoparib against treatment of physician’s choice. Again, efficacy was favoring the PARP inhibitor. Toxicity profiles, I should mention, for PARP inhibitors include some degree of myelosuppression, some degree of GI [gastrointestinal] toxicity, but overall, again as I mentioned for health-related quality of life metrics, favored the PARP inhibitor over systemic chemotherapy.

I will say, again, that these agents were compared to treatment of physician’s choice, but that control arm did not include platinum-based therapy. We really don’t know how these agents would compare head to head up against a platinum. But the control arm did include taxanes and capecitabine and other very typical common regimens for advanced disease.

The BROCADE study looked at incorporating veliparib to chemotherapy backbones. I think, interestingly, here we did see an advantage also to adding the PARP inhibitor to a backbone of chemotherapy. And so, I think more work needs to be done in seeing what optimal combinations there might be.

There are a lot of future opportunities, I think, for PARP inhibitors in the landscape of treating advanced breast cancer. There are combination studies looking at checkpoint inhibitors with PARP inhibitors. There are several studies that are looking at the expanded role of PARP inhibitors outside of germline BRCA mutations.

For example, there is a TBCRC [Translational Breast Cancer Research Consortium] study looking at olaparib in patients with either somatic BRCA1 or BRCA2 mutations or other mutations, either in the tumor or germline, that could be associated with HRD [homologous recombination deficiency] issues. I think there is a lot to be excited about in this space and to keep an eye on.

Transcript edited for clarity.