Comprehensive insight on trial data from OlympiA, which utilized adjuvant olaparib therapy in patients with gBRCA1/2 mutated breast cancer.
Adam Brufsky, MD, PhD: Let’s move on in the interest of time, we could talk about this all day. This is something that both of us like to talk about.
Komal Jhaveri, MD, FACP: Exactly.
Adam Brufsky, MD, PhD: We’ll look at neoadjuvant and adjuvant approaches in HER2-positive breast cancer and TNBC [triple-negative breast cancer]. Again, I think going back for TNBC, we’ve used chemotherapy. For hormone receptor-positive breast cancer, it generally was chemotherapy up until about 15 years ago, when we started to use some of these assays, like the 21-gene [and] 70-gene assay, to stratify patients to get endocrine therapy. The things that are happening now, as we know, we are using these multiparametric assays to omit chemotherapy. I think that a lot of us are not using anthracyclines like we used to, especially in HER2-positive disease, which we may talk about later. I think most people who are T2 and greater will get neoadjuvant therapy for triple-negative breast cancer. We’re going to talk a bit now about immune therapy, BRCA-positive disease therapy such as PARP inhibitors, and high-risk breast cancer as well where we use CDK4/6 inhibitors in the adjuvant setting.
This is the OlympiA trial, which I think most people are familiar with. This was initially presented at ASCO [American Society of Clinical Oncology annual meeting] 2021. Basically, these are women who had a germline BRCA1/2 mutation, they were hormone receptor-positive or with triple-negative breast cancer. They had a bit of a higher risk breast cancer, or they had neoadjuvant chemotherapy but didn’t have a pCR [pathologic complete response]. Again, they were stratified into the neoadjuvant group, which is generally a non-pCR for triple-negative breast cancer or non-pCR with a CPS [clinical and pathologic stage] plus EG [estrogen receptor status and histologic grade] score greater than 3, which I’m going to talk about because I don’t use that. I don’t know if you use that. They had to have at least 6 cycles of neoadjuvant chemotherapy. The adjuvant group was T2, greater than T2, or equal to T2 or greater than/equal to M1 for triple negative, and for hormone receptor positive, they had to have 4 or more nodes positive, and were given 6 cycles of adjuvant chemotherapy.
The bottom line is they were randomized to olaparib for a year or placebo. The primary end point was invasive disease-free survival; the secondary end point was overall survival. This shows you the analysis of overall survival, which was presented at the ESMO [European Society for Medical Oncology] virtual plenary about 2 or 3 months ago, showing an actual survival benefit. At 3 years, the overall survival benefit was 92% in the olaparib arm and about 89% in the placebo arm with a hazard ratio of 0.68.It’s a substantial difference, it’s kind of the difference that we would give therapy for. It’s interesting, I think that a lot of the triple-negative disease is probably driving this, but I think it’s pretty interesting, and this is actually [going to be published] in the not so distant future. In terms of distant disease-free survival, which is related to overall survival specifically in triple-negative disease early on, and you can see here, at 36 months there’s about a 7.1% absolute distant disease-free survival difference favoring olaparib. Thus, with this, let’s talk for a second, this really is driving everybody to do BRCA testing up front.
You [perform testing] in all triple negatives, I’m assuming; do you do it in all triple negatives now?
Komal Jhaveri, MD, FACP: Yes, we try to do it in all triple negatives, or at least the triple negatives that fit the trial criteria, like the patients with T2 or M1 triple-negative breast cancer, but also the additional criteria that we see with triple negative that we think about. But for the ones who fit the trial criteria, we definitely make sure to do it.
Adam Brufsky, MD, PhD: We do the same thing. It used to be under [age] 60, and now it’s everybody. Let’s get to the ER [estrogen receptor] positives, and then we’ll come back to some of the issues with getting this testing. I think that in ER-positive disease, we are at least at our site, using the patients who have a higher family risk for disease, someone with a mother or a sister with disease, or a strong family history otherwise. Are you doing that, or are you testing everybody with ER-positive disease?
Komal Jhaveri, MD, FACP: For ER-positive disease, it’s the highest risk with the family history, which we used to do even before the OlympiA trial. Say it was an Ashkenazi Jewish patient population, it was a strong family history, and we were thinking about that to try to get that in some way. But otherwise, I think we’re only focusing on those patients who would have met the criteria for the OlympiA trial. Thus, it’s the patients with 4-plus nodes or those patients who had residual disease and a CPS+EG score of 3 or higher.
Adam Brufsky, MD, PhD: The CPS+EG score is not something a lot of people are familiar with, can you explain that to people?
Komal Jhaveri, MD, FACP: Yes, sure. I think it’s not that tricky, it sounds more fancy than it is. If you think about it, it’s the clinical stage before neoadjuvant therapy and the pathologic stage after neoadjuvant therapy, in addition to the information of ER status and the grade. They take all of that into account to generate a score from 0 to 6, and the higher the score, the worse the prognosis. The score has been evaluated and validated, and then the 3 or higher is thought to be the highest risk for patients, which is what has been utilized in this trial. It’s just a combination of all that information.
Adam Brufsky, MD, PhD: Got it. I think we’re going to have these triple-negative patients who are going to get; well, I’ll hold off on that question because we’re going to get to that in a few minutes when we talk about the KEYNOTE-522 [trial]. But the issue here is that…I think the big issue with doing all the BRCA testing is the lack of genetic counselors. This not only has therapeutic implications, but actually screening implications for the rest of the family and the patient. Are you finding that may be a limiting factor in ordering these tests? You’re going to have to order them now for therapeutic intent because there’s a survival benefit to PARP inhibitors, but are you finding now that it’s tough? You’re at Memorial [Sloan Kettering Cancer Center], so you probably have as many genomic counselors as you can get, but in the community, do you find people are having trouble finding genetic counselors?
Komal Jhaveri, MD, FACP: Yes, absolutely. I think this is certainly a challenge now that we know that we want to do this, and yes, we want to do it for therapeutic intent. But the implications that that might have on the siblings, the family members, and the screening, that is something that we as a community need to focus on and try to get for our patients. You’re right that I’m fortunate that I don’t necessarily need to worry about that at my institution because we do have that ability. But yes, I think it can be a bit of a wait, and one has to think about this broadly, but it’s important.
Adam Brufsky, MD, PhD: We probably need to think of some out of the box solutions, maybe a lot more telemedicine, a lot more training of genetic counselors. Maybe even some sort of company, either sponsored by the pharmaceutical industry or some sort of company that provides genomic counseling on an ad hoc basis, for people to call in. That’s a great business plan. If one of us wants to stop doing oncology and maybe start a business, a genetic counseling business would help all [of] these people.
Komal Jhaveri, MD, FACP: I think it would be helpful for sure, and I think it’s a great discussion.
Transcript edited for clarity.