Future Roles of PARP Inhibition in Breast Cancer

Transcript:Joyce A. O’Shaughnessy, MD: We now have 2 FDA-approved PARP inhibitors for use in clinical practice in women with germline BRCA, HER2-negative metastatic breast cancer: olaparib and, very recently, talazoparib. And these agents show their highest effectiveness in the earliest treatment of germline BRCA metastatic breast cancer. For example, with olaparib, at AACR [American Association for Cancer Research], Mark Robinson updated OlympiAD and showed that women who received olaparib as first-line treatment versus chemotherapy of physician’s choice had a very large improvement in survival. And there’s also a tail on the survival curve that was very intriguing whereas women who were receiving the PARP inhibitor versus chemotherapy later in the course of their metastatic disease did not have an improvement in survival. These are exploratory analyses, but it was very interesting to see this improvement in survival.

So we want to be using the PARP inhibitors as early as possible in metastatic breast cancer patients who have a germline BRCA mutation, and for triple-negative breast cancer patients whose breast cancers are PD-L1 negative, that would mean we should probably be using olaparib or talazoparib in the first-line setting. For those who have a PD-L1 positive triple-negative breast cancer, there is a survival advantage with the checkpoint inhibitor atezolizumab. So we’ll likely utilize the nab-paclitaxel and atezolizumab, but upon stopping the nab-paclitaxel, it may be very reasonable to add the olaparib at that point, perhaps even along with a checkpoint inhibitor, because we do have adequate safety.

And for patients with ER-positive germline BRCA metastatic breast cancer, we will generally start with an endocrine agent called a CDK4/6 inhibitor. And if the patients have indolent disease and have done very well, we may go on to a second-line endocrine therapy such as alpelisib if they have a PIK3 mutation in breast cancer or everolimus. But if they have more virulent disease, then I think it would be important to get the PARP inhibitor in as a next treatment. Because the sooner we use these, the greater the impact and the more durable the responses will be, and hopefully that will translate into survival for our patients as well.

Transcript Edited for Clarity