Treatment of Germline BRCA with PARP and Checkpoint



Joyce A. O’Shaughnessy, MD: I am very tempted when I have a patient with germline BRCA who is first-line metastatic triple-negative breast cancer to consider the combination of a PARP inhibitor plus a checkpoint inhibitor. We don’t have level 1 evidence for that. We’re getting emerging safety that’s quite reassuring, and the MEDIOLA trial, which combined durvalumab and olaparib, really showed some robust response rates in the 50 plus percent in the very durable responses. It makes a lot of biologic sense in these triple-negative breast cancers that have homologous recombination deficiency. They’re very unstable, chopped up DNA, and then you really chop it up with the PARP inhibitor and activate the STING pathway with cytoplasmic bits of DNA. Then, in come the TILs [tumor-infiltrating lymphocytes] and up goes the PD-L1. Combine it with a checkpoint inhibitor, and preclinical data look very exciting.

We do have the 2 PARP inhibitors now. We’ve got talazoparib and olaparib, both from big phase III trials in the germline BRCA 1/2 population, and both are better than treatment of physician’s choice chemotherapy with 3+ months improvement in median PFS [progression-free survival]. With olaparib, if you give it first-line metastatic before chemotherapy, there’s a nice survival advantage as well. I believe at this meeting with talazoparib, they updated the data as well which are going to pick up more and better outcomes in patients in the first-line setting. I think that’s a really important strategy.

We also saw data at ASCO [American Society of Clinical Oncology] Annual Meeting 2019 combining olaparib with paclitaxel versus paclitaxel and carboplatin looking like the combination of olaparib and paclitaxel, which was quite impressive in the preoperative setting. It was on par with paclitaxel and carboplatin. So, I think we’re going to see a lot of good advances with the PARP inhibitors in combination. But I guess I’ll just ask if you do have a patient with germline BRCA that is also, of course, PD-L1 positive, how are you thinking through that, Erika? What are you doing?

Erika P. Hamilton, MD: I think that’s tough. We don’t have specific data on that. I think you’re out of the data zone at that point, right? I personally think that the benefit with ATEZO [atezolizumab] right now is a higher magnitude of benefit, and we have that approval in the first-line setting. If anything, I personally think that some of the reasons the other trials haven’t been positive is because they’ve been in later line settings. So, in my personal practice, I would give that patient nab-paclitaxel with atezolizumab, and then I would go on to a PARP inhibitor.

Joyce A. O’Shaughnessy, MD: Also, maintenance strategies are going on as well, potentially stopping the IV [intravenous] chemotherapy. If patients have done well, continue the checkpoint inhibitor and perhaps add the PARP inhibitor for patients with germline BRCA. I think that’s an important point you made about the fact that the real survival advantage here is in the first-line setting. I think that’s a really important point.

Transcript Edited for Clarity

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