Adjuvant PARP Inhibitors in Patients with High-risk Early-Stage HER2-Negative Breast Cancer and Germline BRCA Mutations: ASCO Hereditary Breast Cancer Guideline Rapid Recommendation Update

An interview with Dr. Nadine Tung and Dr. Dana Zakalik, co-chairs on "Adjuvant PARP Inhibitors in Patients with High-risk Early-Stage HER2-Negative Breast Cancer and Germline BRCA Mutations: ASCO Hereditary Breast Cancer Guideline Rapid Recommendation Update." They discuss the results and impact of the OlympiA trial, the updated recommendation, and outstanding questions on the use of PARP inhibitors in the adjuvant setting. For more information, visit www.asco.org/breast-cancer-guidelines.

TRANSCRIPT

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ANNOUNCER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines Podcast Series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.ASCO.org. My name is Brittany Harvey, and today I'm interviewing Dr. Nadine Tung from Beth Israel Deaconess Medical Center in Boston, Massachusetts, and Dr. Dana Zakalik from Beaumont Health in Royal Oak, Michigan, co-chairs of the Management of Hereditary Breast Cancer Guideline Expert Panel and this rapid recommendation update, Adjuvant PARP Inhibitors in Patients With High-Risk Early-Stage HER2-Negative Breast Cancer and Germline BRCA Mutations: ASCO Guideline Recommendation Update. Thank you for being here, Dr. Tung and Dr. Zakalik.

DR. ZAKALIK: Thank you for having us.

DR. TUNG: Thank you so much. Pleasure to be here.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online. Dr. Tung, do you have any relevant disclosures that are directly related to this guideline topic?

DR. TUNG: I do receive research funding from AstraZeneca, as I run a trial using a PARP inhibitor in breast cancer.

BRITTANY HARVEY: Thank you. And Dr. Zakalik, do you have any relevant disclosures?

DR. ZAKALIK: I do not.

BRITTANY HARVEY: Thank you. Then let's get into the meat of this rapid recommendation update. So, Dr. Tung, what prompted this rapid update to a recommendation from the Management of Hereditary Breast Cancer Guideline?

DR. TUNG: The OlympiA Trial, which was presented at ASCO this past June and published the same day in the "New England Journal of Medicine." OlympiA was a large Phase III trial, which demonstrated that a year of adjuvant olaparib, a PARP inhibitor, significantly improved both invasive disease-free survival by nearly 9%, and distant disease-free survival by a similar improvement, in germline BRCA mutation carriers with HER2-negative breast cancer and a high risk of recurrence. Overall survival was numerically better with olaparib, but it didn't yet reach significant improvement as a stringent p-value was required for this early reporting.

And I say early reporting because the trial was reported early after the first event-driven interim analysis showed a benefit with olaparib. 1,800 patients had been enrolled with a median follow up of 2 and 1/2 years at the reporting. But the follow up was 3 and 1/2 years for the first 900 patients enrolled, known as the maturity cohort. And it was comforting that the significant improvement in invasive disease-free survival and distant disease-free survival was also seen when just looking at that maturity cohort. So for those who might think that it's too early and that these benefits might not hold up with longer follow up, it's very comforting that in that maturity cohort with longer follow up, the results were really the same.

And last year, ASCO published guidelines on managing patients with hereditary breast cancer, including women with inherited BRCA mutations, meaning a pathogenic or likely pathogenic variant. At that time, PARP inhibitors were recommended only for BRCA carriers with metastatic disease, based on the OlympiAD and EMBRACE trials. So when OlympiA was published, we felt the need to update the guidelines to recommend olaparib in the early-stage setting for some germline BRCA carriers.

BRITTANY HARVEY: So then, based off this new data from the OlympiA trial, Dr. Zakalik, what is the updated recommendation from the guideline expert panel?

DR. ZAKALIK: The updated recommendation states that for patients with early-stage, HER2-negative breast cancer with a high risk of recurrence, and who carry a germline BRCA1 or 2 mutation, one year of adjuvant olaparib should be offered after completion of adjuvant or neoadjuvant chemotherapy and local treatment, including radiation therapy. And this data was specific to a high risk of recurrence subgroup of these patients, defined as, for those with triple-negative breast cancer having a tumor over two centimeters, or with any involved lymph nodes, or for those who received neoadjuvant chemo, any residual disease in the triple-negative setting was sufficient to qualify.

For patients with hormone receptor positive disease, these were high-risk patients for recurrence, again, and that was defined as having at least four positive lymph nodes, or any residual disease following neoadjuvant therapy. But in addition, having a clinical stage and pathologic stage estrogen receptor status and tumor grade, otherwise called the CPS+EG score, of greater than or equal to three, which is really defined as looking at estrogen receptor status grade and clinical and pathologic stage. So again, a high-risk group for risk of recurrence was included in this study. And again, in order to apply these findings, we have to be mindful of patients who meet these inclusion criteria as being high-risk for recurrence. Again, both in the triple-negative hormone receptor-positive setting, if they met these criteria, there was a significant benefit in terms of outcome in lowering the risk of recurrence.

BRITTANY HARVEY: I appreciate you going through that recommendation. So then, given that updated recommendation. Dr. Tung, what should clinicians know as they implement the use of adjuvant olaparib into clinical practice?

DR. TUNG: For those who have not used olaparib, it's worth saying that it's an oral medication. Typically patients take two pills twice a day. And it's important to be familiar with the side effects. I would say that generally, olaparib is well-tolerated. But it can have side effects. And the two most common are nausea, and then anemia. So for the nausea, we use the typical antiemetics we would use for any chemotherapy. And it's worth saying to patients who do have nausea that quite often, that lessens with time. It decreases. So I would say nausea's one of the side effects. Some patients can have fatigue, although I don't think that's all that common.

And anemia is the other one. And we do check bloodwork monthly for patients on olaparib. The anemia can come suddenly, even after months of really not having any. And grade 3 anemia was probably the most common, grade 3 or higher, toxicity that was seen in OlympiA, although it's only 9% of patients that had grade 3 or higher anemia. But I would say those are the two side effects to look for most. And then I think one other thing that's worth saying is that for the BRCA carriers with triple-negative breast cancer, currently our standard therapy for patients who have residual disease after neoadjuvant chemotherapy is capecitabine. But olaparib should not be given with capecitabine. There is no safety data for that. So oncologists are going to need to choose between what I think is our standard therapy right now, capecitabine, and olaparib. And there's no data directly comparing these two medications in the early-stage setting.

But in the metastatic setting in BRCA carriers, in both OlympiAD and EMBRACE, olaparib was compared to chemotherapy. And olaparib with superior. And in both of those studies, about half the women in the chemotherapy arms received capecitabine. And olaparib, again was superior. So olaparib may be the better choice in the early-stage setting. But I can't say that there's any direct data. But the message would be not to give them together. And I think it would be better probably not to give capecitabine first and then olaparib, because there's some data that the earlier you give a PARP inhibitor the better.

BRITTANY HARVEY: Those are important notes for clinicians and particularly for safety. So then building on that, Dr. Zakalik, how will this update impact patients with breast cancer?

DR. ZAKALIK: This data will significantly impact the therapeutic options that we have for patients with high-risk disease in the setting of a BRCA germline mutation. And that will happen in the sense that patients who have these certain specific features that render them high-risk will now be able to be offered a very impactful therapy that has been shown in this landmark study to significantly decrease their risk of recurrence. And these are patients who otherwise would face a significant risk of potentially facing a recurrence in the future. So the outcomes we anticipate to be dramatically improved for patients who have triple-negative or high-risk hormone receptor-positive breast cancer in the setting of a BRCA germline mutation.

But furthermore, whereas genetic testing in the past was predominantly focused on identifying individuals who are at high risk for developing breast cancer so that we can offer early detection or prevention options, this is the first time that we're able to broadly apply the benefit of molecular genetic testing for hereditary risk to therapy for patients with early nonmetastatic breast cancer. So as clinicians who see patients with breast cancer, it is further made more important to recognize what the guidelines are for genetic testing. To think of whether a patient meets criteria that are currently outlined for genetic testing, as this will have a significant potentially major impact on patients' outcome. And already in the clinic, we have been focused on recognizing who may have a BRCA mutation. Obviously, this data will make that even more important, because this therapy is so beneficial for patients. And I think going forward, it will fuel a discussion of possibly reevaluating who gets genetic testing, now that it's particularly important not to miss patients who have BRCA mutations when they develop breast cancer.

So I think that physicians who are in the clinic will not only have a therapeutic option, but also will be hopefully recognizing more patients who have a BRCA mutation in that the therapy is so markedly better now with this new data. And in the future, we may possibly expand our guidelines for testing. And I think that remains to be determined, based on a number of factors that go into this decision.

BRITTANY HARVEY: Well then, you've both touched on this a bit, regarding outstanding questions for both genetic testing and the use of capecitabine. But finally, Dr. Tung, given this recent study and guideline update, what are the outstanding questions regarding the use of PARP inhibitors in the adjuvant setting?

DR. TUNG: Right. We have already listed a couple. The capecitabine question is one that I won't repeat. And I think who gets tested would be another one that Dana just mentioned. I think a big one, as of yesterday, is immune therapy. Yesterday, the FDA approved pembrolizumab, based on the KEYNOTE-522 study for patients with triple-negative breast cancer. And that population in KEYNOTE was very similar to the one in OlympiA for BRCA carriers, namely patients with T2 tumors, or involved axillary lymph nodes. So for BRCA carriers, we're going to have to make some decisions here, namely, should they receive pembrolizumab and olaparib together, for those who have residual disease after neoadjuvant chemotherapy. I think everyone right now is digesting KEYNOTE-522 and this FDA approval. And so that's something that will have to be worked out.

I know in other diseases there is safety data for the combination of pembrolizumab and olaparib. But again, I think that's something that we're all going to have to sort out. I don't think there's going to be any data forthcoming immediately about the use of pembro, olaparib, and the combination, et cetera for our patients. So that's a big one I think another question that comes up is, how long after a BRCA carrier finishes their chemotherapy and local therapy are they eligible to take olaparib? What about patients that finished six months ago, or a year ago, or longer? And again, I don't think there are any data for that, and we're going to have to use some clinical judgment. There was precedent for this kind of question when adjuvant trastuzumab was approved and in 2005, when the adjuvant trials demonstrating such an impressive benefit for trastuzumab were announced and published.

I remember that we were administering trastuzumab to patients who'd completed their chemotherapy within the last year. So I think for many, that may be a timeline that makes sense. But again, there are no data. So still questions, and we're going to as always have to use some clinical judgment. And others, Dana, that you can think of?

DR. ZAKALIK: No. I think this is tremendously exciting new data. It really provides hope for patients who are young, often, when they're diagnosed. Because hereditary breast cancer tends to manifest itself at a young age. And so for our women in the prime of their life, when they have high risk and develop breast cancer, I think this just really gives us tremendous hope and opportunity for improving the lives and saving lives in the future of patients who have high-risk disease. Very exciting data.

DR. TUNG: Yeah, I agree completely. I think the investigators are really to be congratulated. This was a very large study. 1,800 BRCA carriers, international study. Very hard to do with a situation, a disease that's relatively uncommon. Only 3% to 5% of all breast cancer. So really a terrific effort with a significant, major impact for our BRCA carriers with breast cancer.

BRITTANY HARVEY: Definitely. This is an exciting update for patients with breast cancer. And we'll look forward to hearing more research about those outstanding questions that you mentioned. So I want to thank you both for your efforts to update this guideline recommendation so quickly, and provide evidence-based recommendations for both clinicians and patients. And thank you for taking the time to speak with me today, Dr. Zakalik and Dr. Tung.

DR. ZAKALIK: Thank you.

DR. TUNG: My pleasure.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. For more information, visit www.ASCO.org/breast-cancer-guidelines. If you have enjoyed what you heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

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