Role of PARP Inhibition and I/O Therapy in TNBC

The use of PARP inhibitors and I/O therapy is examined for the treatment of triple-negative breast cancer, and the MEDIOLA and SWOG S1416 trials are reviewed.

Transcript

Hope S. Rugo, MD: Now that we have PARP inhibitors approved for patients who have BRCA-mutated metastatic disease, there’s been a lot of interest in combinations of therapy with PARP inhibitors and checkpoint inhibitors. Priyanka, do you want to comment a little about the hypothesis behind combining these agents?

Priyanka Sharma, MD: As you said, for PARP inhibitors, we’ve had them available to treat our patients with HER2-negative metastatic breast cancer—that is, in the setting of germline BRCA1 or BRCA2 mutation. There are robust preclinical data to suggest combining a PARP inhibitor with a checkpoint inhibitor might help improve on the patient population that’s eligible for PARP inhibition, beyond those that carry a germline mutation. Several postulated mechanisms have been proposed perhaps by increasing antigen load and increasing PD-L1 expression. Maybe having a PARP inhibitor on decreases the capability to repair damaged DNA. That damaged DNA might induce some local lymphocyte infiltration, some type of innate immunity, so several mechanisms. Based on that, there are a couple of trials that looked at the combination.

The first cohort of the MEDIOLA trial looked at patients with a germline BRCA1 or BRCA2 mutation and combined a PARP inhibitor olaparib with durvalumab. You’ve seen several presentations on that over a period of time. The last 1 I think was in San Antonio Breast Cancer Symposium in 2019. MEDIOLA included patients who were in the first line and beyond settings. It reported impressive response rates, about 70%. When you looked at the patients who were first line and second line, it was a little bit lower as you went further along. But we’ve seen that individually for both PARP inhibitors and checkpoint inhibitors, the further along we get for a metastatic timeline, the decreased the response rates. Again, this is a single-arm study. I understand that they have an expansion cohort ongoing, but what would be needed would be a randomized trial.

Hope S. Rugo, MD: Yes, it is interesting. There is a randomized phase 3 trial called KEYLYNK-009, which is looking at patients in the first-line triple-negative setting regardless of BRCA mutation or HRD [homologous recombination deficiency], so not stratifying based on HRD. Patients receive gem-carbo-pembro [gemcitabine, carboplatin, pembrolizumab] and then are randomized to either continue with that or to receive olaparib and pembro [pembrolizumab] as a maintenance approach based on some of this idea that you might upregulate the immune response. Whether that will be changed based on the data from KEYNOTE-355 remains to be seen.

It will be interesting to understand that based on when we finally see that data presented in a setting. Another question that comes up is, how do you decide whether to start with the I/O [immuno-oncology] or a PARP inhibitor? If you have a patient who has PD-L1-positive disease, who has metastatic triple-negative breast cancer, what do you choose? Claudine, what do you choose in that setting?

Claudine J. Isaacs, MD: We’re talking about nonmutation carriers? Not patients who have germline mutations?

Hope S. Rugo, MD: No, this is if a patient has the BRCA mutation, has triple-negative metastatic breast cancer, and presents with PD-L1–positive disease.

Claudine J. Isaacs, MD: Those are difficult choices. I don’t think there’s a right or wrong answer. I just had a patient like that a few months ago, and we had that discussion. The ideal thing is to put them on a trial where they can get a PARP inhibitor and immunotherapy at a checkpoint inhibitor. That’s available at some sites but not for all patients.

Given that the immunotherapy data that we have at hand are most impressive when they’re done earlier on in line, and the PARP inhibitor therapy was often in patients who had received more treatment or potentially allowed more than first line, in all those settings the benefit is greatest in the first-line setting. So you really have to make an individual choice. I think one might choose immunotherapy in first line and then go to a PARP inhibitor. But the ideal thing in patients like this is to put them on a combination if you have that available.

Hope S. Rugo, MD: Many people would choose an I/O first for the survival part, but then of course you want to throw in the PARP inhibitor relatively quickly so then that’s a big challenge. Having these trials with the maintenance will be really helpful. Priyanka, I know you’re 1 of the leaders of the breast cancer group for SWOG, and they did a PARP inhibitor trial in patients who have BRCA wild-type disease. I don’t know in what subpopulation, but maybe you could tell us a little about that and when we can expect results.

Priyanka Sharma, MD: SWOG S1416 was a randomized trial that focused on patients with BRCA wild-type disease to look at the efficacy of PARP inhibitors when added to a chemotherapy backbone that included platinum. The focus of this trial was to look at the efficacy of PARP inhibitors in the patients with HRD. HRD was defined using tissue biomarkers to look at the patients who don’t have a germline BRCA mutation but biologically have other changes that suggest that they are deficient in repair capabilities. It was a phase 2 trial, and it will be presented at the virtual ASCO [American Society for Clinical Oncology] Annual Meeting this year.

Priyanka Sharma, MD: For immunotherapy, we had to first identify the patients who will have BRCA wild-type disease and are able to derive benefit from PARP inhibitor and then add immunotherapy there.

Hope S. Rugo, MD: For our audience, will that be 1 of the oral presentations?

Priyanka Sharma, MD: Yes, it will be.

Hope S. Rugo, MD: That’s great. We’ll look forward to that. Congratulations, and indeed, that will be a really interesting presentation to hear about, 1 we’re all interested in.