Behind the FDA Approval: Adjuvant Olaparib for BRCA+/HER2- Breast Cancer

Charles Geyer, MD

Recently, investigators of the phase 3 OlympiA study discovered an overall survival (OS) advantage with adjuvant olaparib (Lynparza) compared with placebo in patients with germline BRCA-mutated, HER2-negative, high-risk early breast cancer, which led to the FDA approval of this indication.

According to results presented during the March 2022 ESMO Virtual Plenary, adjuvant olaparib achieved a 32% reduction in the risk of death compared with placebo after a median follow-up of just 3.5 years (stratified HR, 0.68; 98.5% CI, 0.47-0.97; P = .0009). The finding was statistically significant and was paired with a manageable toxicity profile.

The most common adverse events (AEs) observed in the study were nausea (56.9%), fatigue (40.1%), and anemia (23.5%), while in the placebo arm, the most common any-grade AEs were nausea (23.3%), fatigue (27.1%), and headache (16.8%). Common grade 3 or higher AEs reported were anemia (8.7%), decreased neutrophil count (4.8%), decreased white-cell count (3.0%), fatigue (1.8%), and lymphopenia (1.2%). There were also some serious AEs in 8% of patients.

In an interview with Targeted Oncology™, Charles Geyer, MD, medical oncologist/breast cancer specialist, and chief scientific officer, NSABP, discussed the data from the OlympiA clinical trial and how adjuvant olaparib could impact the treatment of BRCA-positive, HER2-negative breast cancer and other BRCA-positive women’s cancers.

TARGETED ONCOLOGY: Can you talk about olaparib and what sets it apart from other PARP inhibitors?

Geyer: Olaparib is a first-in-class drug. In the early breast cancer setting, there are a number of these PARP inhibitor drugs. There's actually 4 or 5 that have been approved by the FDA across different tumor types. Two of them have been approved in metastatic cancer: olaparib and talazoparib [Talzenna]. They are approved specifically for patients who have germline BRCA mutations which cause cancers that develop in them to be unusually sensitive to inhibition of PARP. Basically, a cancer that's developed in a patient who has a germline BRCA mutation will lose all of the BRCA protein function, which is important in repairing DNA and even cancer cells have to kind of repair their DNA as they're dividing, or things can just get too chaotic. So, they become addicted to PARP. And PARP inhibitors then shut that off. And they are basically overwhelmed by too much instability in their DNA in the genome. So, they will die. That’s why these drugs have been active across a number of tumor types like breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, and got approved in the metastatic setting.

What is new about the OlympiA study result is that this is the first time these drugs have been taken into the early breast cancer setting to see if we can decrease recurrences, reduce deaths, and OlympiA is telling us that, yes, we can. And we use olaparib after patients who receive all their standard treatments for early breast cancer. So that's the uniqueness of it. It's the patient population of those with germline BRCA mutation who developed breast cancer that is higher risk. So, the standard therapies are a bit lacking for them. And we were looking for something to get in addition to it. And we've now demonstrated that something is olaparib.

Can you discuss the efficacy findings from the OlympiA trial?

The primary end point for OlympiA was actually presented at the ASCO Annual Meeting 2021 almost a year ago. That was when we conducted the initial interim efficacy analysis. And what we saw at that point was that olaparib relative to placebo was already showing a meaningful and statistically significant improvement, and our end point called invasive disease-free survival is actually a composite end point that is describing a group of women who are alive and free of any breast cancer or any other type of cancer. But it's an important one, because it helps us get a sense of both efficacy and safety.

What we saw at that point, with about 2.5 years of median follow-up was that the group of women who had had standard therapy, but then received placebo, 23% of them had already had a recurrence or had died. So, that's kind of what we were targeting in our patient population, we thought, okay, let's look at patients who are on standard therapy, still have invasive disease-free survival rates at 3 years of less than 80%. We saw that in our control group. So, we were successful there.

Happily, in the patients who had received the olaparib, that 77% increased up to 86%, and absolute 9% improvement, so a very gratifying step up for staying alive and cancer free. We also did the study to specifically then look at and really focus on the most feared part of breast cancer, and that is cancer that comes back out in the body, distant metastasis, because that's what will take a patient's life. And we saw virtually the same sort of improvement. The percentage of patients who were alive and free of distant metastases was 81%, it went up to 88%. So again, it was a very meaningful improvement.

Now, at that early point, our survival question, just looking at how many patients are still alive, we saw that patients getting olaparib seemed to be doing better. But it was early enough in the study that we needed more follow-up to really be sure if that apparent reduction in deaths was statistically valid. What we reported on recently during the ESMO Plenary and what the FDA basically included in their approval was that yes, survival is also improved by about an absolute value of 3.5%. We expected that probably will get larger over time, because we know when patients develop distant disease, unfortunately, our therapies aren't able to cure it. So though that 7% difference is there, we think, probably will lead to improvement, but we already are seeing a meaningful improvement with the olaparib. So, the efficacy side of the drug is quite strong at an early point in the trial analysis.

The relevance of BRCA status is an important research question. Why is it important to know BRCA status if it’s not prognostic and what prognostic factors should oncologists be looking for?

Patients who have a germline BRCA mutation don't do worse than those with the normal so that is something to make sure that people aren’t misunderstanding when we talk about higher risk. The reality is that the types of cancer that developed in patients with these mutations tend to be among the more aggressive types that tend to present with more advanced stage. So, what we did in Olympia was we targeted women who still had higher risk, women who had triple-negative breast cancer that was either larger than 2 centimeters, what we call a T2 or T3 tumor with negative lymph nodes or anybody with positive lymph nodes. Or now what's much more common is we give with women and men with triple-negative breast cancer their chemotherapy first and see if the cancer completely goes away in the breast, we'll be calling pathologic complete response, because if it does, we know they actually do quite well. The patients with residual disease though where the tumor didn't get rid of it have higher risks. So that was the other way that patients were able to enter into OlympiA with a triple-negative breast cancer. But not all women who have BRCA mutations develop triple negative [disease]. Some develop ER-positive HER2-negative [breast cancer], so we also included them when their degree of

risk was comparable to what the triple-negative patient population was.

So, we know that the BRCA per se doesn't give you a worse prognosis. But in order to define the prognosis, you have to understand what the risks are of the disease. And those relate to the size of the tumor, lymph node status, did they respond to the chemotherapy, yes or no to neoadjuvant therapy and things like that.

Can you discuss the safety profile of olaparib in OlympiA. was there anything interesting?

We knew from the metastatic patients where a lot of the initial studies had gone on that it was likely that we would see patients challenged with milder degrees of nausea as their GI system gets used to the medication. And so, we did see that a common adverse event was milder grades of nausea grade 1/2. On the trial we recommend, and still do recommend that when patients take the medication, which they take 2 a day, they should take it with a small amount of food or snack that seems to really help with that transition process. We did not see a lot of patients stop the medication because the nausea persisted because it was something that they couldn't figure out how to manage. So, we view that as an initial challenge, where it's important to work together with the patient to you know, work on taking it with food remembering to take it.

The other common adverse event is anemia, and you do have to monitor blood work. Sometimes patients will require a dose reduction, the stamp, the starting dose is 300 milligrams twice a day, some patients do better at 250 milligrams a day. In terms of their anemia, we did occasionally have to provide transfusions for some patients. But overall, we were pleased that the profile was one of favorable tolerability, and relatively few discontinuations for an oral therapy going on for a year after a patient is completed months of chemotherapy surgery, we were pleased with it.

In the trial, we also included patient-reported outcome analyses, which were reported at the San Antonio Breast Cancer Symposium, based on the assessment of the women on the study, it really did show that adverse events were minimal and resolved when they stopped the medication. So, we feel like the information that we have is shows substantial potential benefit, manageable adverse events. We think that's a favorable situation for patients to at least carefully consider and think about a trial of the therapy.

What advice do you have for your peers on how to manage the grade 3 or higher toxicities and any serious AEs that were observed in the clinical trial setting, in the clinic?

It's primarily the GI and the anemia, and I think the important thing for my colleagues will be to remember first few months are the important months where you do need to monitor the lab work. We had conservative criteria in OlympiA in terms of the hemoglobin, if it dropped down below 9 and a half, we recommended that the drug be held and wait for the hemoglobin to come up. If it comes back quickly, in a week or 2, go back to the starting dose if it takes longer than reduce the dose levels. So, I think that early attention to monitoring the CBC and giving patients breaks, because it's a year of therapy. So, they have to find the dose that's right for the individual patient. And then, the patient will have a much better chance of tolerating it well and being able to complete a year of therapy. If there is substantial anemia, transfusion for once or maybe twice should be considered but if women are having that much difficulty in the curative setting with the drug, then stop it but for those adverse events [in the study] were relatively few.

What is the potential impact of adjuvant olaparib on the treatment landscape?

I think it's a very important development for the patients who have been living with not only do they have breast cancer, but they also have this cancer predisposition gene. There's long been an understandable frustration about well they have this kind of special sort of cancer that develops, it comes on early bilateral reality, there's other risks. So, I think it's exciting story that the abnormality that caused the cancer also now is a special vulnerability to the right kind of therapy. So, it's an exciting story about how basic translational science working to really understand what does it mean to have a BRCA mutation? Why did the cancers develop? How do they develop how they might be vulnerable? It's a nice story and shows how the science and then the broad clinical research community working together with our patients with our advocates can really bring us significant advances. So, I think this is a big step forward.

We will continue to follow OlympiA because we want to know what the median follow-up looks like later on. Could taking this drug reduce the chances of getting a second cancer patient with a BRCA mutation? It looks like we've taken care of the patient’s first cancer, but they’ve still got risk for other cancers, is there something that might reduce that risk? These are things that we will still be able to learn from OlympiA, and we're going to be studying carefully where patients are willing to have their tumors sent into the research group, so we can keep working on and improving things.