Selecting PARP Inhibitors for Patients With ER-Positive Early Breast Cancer

Systemic Treatments for ER-Positive Early Breast Cancer: Part 3

In this expert roundtable series, Cynthia Ma, MD, Washington University School of Medicine, St Louis, Missouri, leads a 4-part roundtable panel discussion on updates in selecting the optimal treatment for ER-positive early breast cancer with Neelima Vidula, MD, Massachusetts General Hospital, Boston, Massachusetts, and Seth Wander, MD, Massachusetts General Hospital.

In part 3 of this discussion, our experts explore the use of PARP inhibitors, focusing on sequencing and patient selection.

Transcript:

Dr Cynthia Ma:
Dr Vidula, would you like to comment on how do you select patients for PARP inhibition and the data behind that?

Dr Neelima Vidula:
Thank you, Dr Ma. We have the opportunity to offer a PARP inhibitor, olaparib, to patients that have germline BRCA1/2 mutations in the adjuvant setting with early-stage breast cancer, including ER-positive, HER2-negative disease. That’s actually based on the OlympiA study, which was a phase 3 study that enrolled patients with HER2-negative, early-stage breast cancer who had a known germline BRCA1/2 mutation. Germline BRCA1/2 mutations account for about 5% to 10% of breast cancer. It is important to screen patients, particularly younger, for this mutation since we now have the availability of a targeted therapy, and it may also affect surgical decision making.

In this study, all the patients who were enrolled had completed local therapy, including radiation, and they should have received at least 6 cycles of chemotherapy, either in the neoadjuvant setting or in the adjuvant setting. In the neoadjuvant setting, if they had received chemotherapy, then they should not have had a pathologic complete response. They looked at many criteria including pathologic complete response, ER-positivity, and grade to help select patients in that setting. For patients who were getting adjuvant chemotherapy with ER-positive, HER2-negative disease, they had to have at least 4 lymph nodes involved. Patients who met criteria were then randomized in a 1-to-1 fashion to treatment with olaparib for 1 year or placebo. And with the addition of olaparib, the 3-year disease-free survival was 85% compared to 77% in the arm that received placebo. In addition, the 3-year distant disease-free survival was 87.5% with olaparib versus 80% with placebo. They did observe less deaths in the cohort that received olaparib, but this was not yet statistically significant, so we'll await longer-term follow-up on that.

In summary, patients who have a germline BRCA1/2 mutation with ER-positive, HER2-negative disease who fit criteria for either having 4 positive nodes or having received neoadjuvant therapy without a pCR and having some of those higher-risk features are eligible for treatment with adjuvant olaparib, and that would continue for a year.

Dr Cynthia Ma:
Thank you, Dr Vidula. Dr Wander, a lot of these patients with BRCA mutations that fit the criteria for eligibility for a PARP inhibitor may also be eligible for adjuvant abemaciclib. How do you decide on one versus the other, or do you do both?

Dr Seth Wander:
It’s a great question. It's an edge case, but it's a case that we've certainly discussed at our tumor board a number of times. We have new opportunities for these kind of higher-risk patients and It's always a good challenge to have multiple things to choose from. I think certainly I would not give them concurrently. We don't have safety data to give them together. And you definitely would be worried about compound risk of cytopenia with both and perhaps GI toxicity. It’s a bit of dealer's choice. We don't really have any prospective data about sequencing these agents.

Many folks might opt to get the PARP inhibitor done first, because it's only 1 year. And if you think about it, it's sort of a more personalized treatment for the patient based upon, as Dr Vidula was saying, the presence of their germline BRCA mutation. I don't think it would be wrong, necessarily, to give it in the other direction because again, I don't think we have a lot of data for that. Given the data that we do have for the 1 year of the PARP inhibitor, most of us probably would utilize that first.

Dr Cynthia Ma:
Yes, that's probably what I would do as well. Usually, I would probably choose PARP inhibition first, and if the patient is still is motivated to be CDK 4/6 inhibitors, I might consider that as well for really high-risk patients. Dr Vidula, do you have any comments on this?

Dr Neelima Vidula:
This is a tough one, but it actually doesn't come up that commonly, since the frequency of germline BRCA 1/2 mutations is not that high. In general, with in this type of situation, I have tended to reach for the PARP inhibitor, just thinking that it is a targeted therapy directed towards the BRCA1/2 pathway for those patients. There's definitely no combination data right now to combine the PARP with abemaciclib. But if you have the right patient who was motivated and had very high-risk disease, I think it would be reasonable after completing the PARP to consider the abemaciclib. It is worth noting that you can combine the PARP inhibitor with hormone therapy. We think that that's pretty safe. I have done that in my practice.

Dr Cynthia Ma:
Yes, that's a great point.