Sara A. Hurvitz, MD: The ongoing OlympiA clinical trial is the first study to evaluate the use of a PARP [poly adenosine diphosphate-ribose polymerase] inhibitor in the curative setting in a randomized clinical trial. This study was designed for patients with either hormone receptor-positive or triple-negative high-risk breast cancer, who were known to have a BRCA1 or BRCA2 mutations, and had stage 2 or stage 3 breast cancer or a lack of pathologic complete response [PCR] to neoadjuvant chemotherapy. They were randomized to receive olaparib or placebo for 1 year. The dose of olaparib was 300 milligrams twice daily. You can see by this study design slide that it's a bit complicated who qualified. For the triple-negative patients who'd had neoadjuvant therapy, they had to have a non-pathologic complete response [PCR]; for the hormone receptor-positive, they had to have a non-PCR and a clinical prognostic score with an EEG [electroencephalograms] score of at least 3, they had to have received at least 6 cycles of neoadjuvant chemotherapy, and receive surgery with or without radiation. In the adjuvant group, the triple-negative patients had to have larger tumors PT2 or node-positive; and for hormone receptor-positive, they had to have at least 4 nodes involved. These are high-risk patients—and if you go to the next slide, you can see the baseline characteristics of patients enrolled in this clinical trial. Patients are younger in this study, all the patients have BRCA mutations, and this tends to affect younger women at diagnosis, around 42 to 43 years old in each of the arms. Most of the patients have BRCA1 mutations in this study—just over two-thirds of patients. BRCA2 is carried by about a quarter of patients. Previous adjuvant chemotherapy was given to about half of the patients, and previous neoadjuvant therapy in about half of the patients. The triple-negative breast cancer subtype made up most patients enrolled in this study. Roughly 80% of patients have triple-negative disease compared with hormone receptor-positive in HER2-negative breast cancer.

The next slide will show you the outcome that was reported at a March 2022 ESMO [European Society of Medical Oncology] virtual plenary session. It shows you the invasive disease-free survival [IDFS] and the overall survival. The invasive disease-free survival is the Kaplan Meier curve seen there. You can see a nice and early separation of the curves in terms of IDFS in favor of olaparib. It’s nice to see the curves continue to separate over time. If you're looking at that 36-month time point, about 86% of patients are free of an invasive recurrence in the olaparib arm compared with 77% of patients—a nice difference that makes you feel good about using a drug for a year after surgery. At the same ESMO virtual plenary in March of this year, with the median of 3 and a half years of follow-up, the 3-year overall survival rate is 92% with olaparib, 89.1% with a placebo, with a hazard ratio of 0.68. This is now available. Some of us were using this outside of the United States Food and Drug Administration [FDA] approval because we have it for use in the metastatic setting, but we recently had it made available by FDA approval for patients who are carriers of BRCA mutations and are found to be high risk. This is important data. The distant disease-free survival [DFS] is shown here. On the left, you can see there's this hierarchical design where first you had to prove statistical significance for invasive disease-free survival. They met that end point. They also showed significance for distant disease-free survival by meeting the P value of less than 0.005. As you can see, the hazard ratio is 0.57, a nice separation of the curve: 7% delta at 3 years, and then overall survival had to be less than 0.01. They made a grand slam home run. All 3 end points were met. Although the population of patients who are affected by BRCA mutations is small in the world of breast cancer, these are important findings, especially for our patients with triple-negative BRCA-associated cancer, where the outcomes are poor.

Joyce A. O'Shaughnessy, MD: Yeah, really important data. Great to see survival. We don't get to see that too often. It's fairly early in the follow-up of these breast cancers, but this is an aggressive subtype. It's great to see the impact on survival. I was pleased to see that this is well tolerated, and happy to see no increase in AML [acute myeloid leukemia] or MDS [myelodysplastic syndromes] with this agent. I was also pleased to see that although the numbers are very small, there's a trend towards decreased second malignancies in this population. We're going to watch that with great interest as the follow-up continues in these patients. This is a must-do for our patients with a known germline BRCA1 or -2, who are high-enough risk to meet the eligibility for the OlympiA trial. That's the challenge I'm having in my practice finding these patients. I'm still plugged into the NCCN [National Comprehensive Cancer Network] guidelines of age and family history, if you're on TMBC, under 60, et cetera. One could argue that given this improvement in the magnitude of improvement in IDFS, DFS, and survival, that we wouldn't want anybody with this. Who do you think we should be testing? And how do you do it in your practice?

Sara A. Hurvitz, MD: I try to test as many people as I can, to be quite honest. We have genetic counselors embedded in our clinic; we're fortunate enough to have that. With genetic testing being a lot more affordable, even those patients whose insurance doesn't cover them, they're able to get it now that we have a drug, and it's not just that the BRCA mutation would affect family members or surgical decision-making. Now that we have a drug that's proven to help our patients who have BRCA mutations who are especially high-risk, I try and get them tested. The only patients where we wouldn't use this are those with HER2-positive disease, and the frequency of BRCA mutations in that patient population's relatively low. Sometimes BRCA2 mutations, but it's unusual to have a BRCA1 mutation. I look for reasons to test, and I’m careful about those patients in whom testing is not done. Your patient who's over the age of 65 with zero family history and an ER-positive small tumor is not going to be a high priority, but for a lot of my patients, we will be able to get it even if they don't strictly meet the NCCN criteria. What about you?

Joyce A. O'Shaughnessy, MD: I like your point you just made about the risk because if they've got the family history, the young age, my algorithm is down there. I’ve got that 1 down pat. I must encourage people 2 and 3 times sometimes or send the referral 2 and 3 times. That's fine; I'm happy to do it. It's on my list; I won't forget it. There are patients where they're just a little bit older, they don't have the family history, and it might slip through my cracks. In the algorithm, we think, This is a high-risk patient; this patient's got node-positive disease; this patient's got a big cancer; this patient's got grade 3, where you've got risk; and you're thinking, What can I optimize for this patient? That's another avenue to get to germline BRCA1, -2 testing because we're going to be thinking about pembrolizumab. We're going to be thinking about, Do they fit abemaciclib? And now can we give them that? Will they ever benefit from olaparib? Another way to get there is, I have high-risk patient; what can I do for this patient?. I'm still in evolution enlarging that window so I don't miss anybody who could benefit based on the OlympiA data. It is a little bit of a work in progress. I want to come back because we need to put olaparib into the context of the option of abemaciclib and the option of adjuvant pembrolizumab. We'll come back to that and talk about our practice pattern once we go through the next couple of data sets—these other big adjuvant and neoadjuvant trials. This is a must-do. We must figure it out, find the patients, and make sure that if they fit the OlympiA data, that they get this agent, essentially.

Transcript edited for clarity.