Redefining Care for Breast Cancer Patients: Clinical Perspectives on the Impact of OlympiA and OlympiAD

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Hi, my name is Dr Priyanka Sharma.

The breast cancer treatment landscape is continuously evolving thanks to our broadening understanding of the value of precision medicine. And of course, when we think about precision medicine, one of the very effective treatments that we think about is LYNPARZA. It’s amazing that LYNPARZA has been available to patients with certain types of breast cancers for quite some time now.²
As the first approved PARP inhibitor for patients with germline BRCA mutation-associated metastatic breast cancer, and the only PARP inhibitor approved for gBRCA mutation-associated early-stage breast cancer, LYNPARZA represented a significant treatment advance for patients with germline BRCA1 or 2 mutation, giving them a targeted treatment option that was not previously available.^1,2

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In 2017 the first phase 3 trial of LYNPARZA in breast cancer was published. OlympiAD, compared LYNPARZA with standard-of-care chemotherapy in patients with gBRCAm HER2-negative metastatic breast cancer. This study showed that LYNPARZA was superior to standard-of-care chemotherapy in terms of progression free survival.^1,3

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The results from the OlympiAD trial led to the 2018 approval of LYNPARZA for patients with gBRCAm associated HER2-negative metastatic breast cancer, which allowed us to use this effective oral medication in clinic.^1,2

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BRCA-associated breast cancers represent 5-10% of all breast cancers. However, breast cancer is a very common cancer. So, in sheer numbers, 5-10% of breast cancers represent modest number of patients that we see in clinic.^4,5

Prior to the approval of targeted therapy, genetic testing was primarily limited to counseling for second cancers, cascade testing the family members, preventative strategies, etc. But once targeted therapies were approved, genetic testing information became important for making cancer treatment decisions. This meant that patients needed information and access to genetic testing in a time-sensitive fashion. Many models of point-of-care testing with support from physician extenders are now used in clinic. The goal is to provide rapid access to testing for all eligible patients, even if genetic counselor services are not readily available.⁶

With BRCA mutation-associated breast cancers, the approval of LYNPARZA led to a change in guidelines to recommend testing for germline BRCA1/2 in all patients with metastatic breast cancer, as there was an available targeted treatment option. This led to shift in how we think of genetic testing in clinical practice, which was good for our patients.^6,7

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As we started to gain experience with LYNPARZA in our patients with BRCA-mutated metastatic breast cancer, the high-risk early stage breast cancer trial, OlympiA began enrolling patients with germline BRCA mutated, triple negative or hormone receptor positive HER2-negative breast cancer.^1,8

This was a monumental trial and a significant international effort to test the efficacy of LYNPARZA in curative setting.⁸

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Results from the landmark OlympiA demonstrated clinically meaningful improvement in disease free survival and eventually also clinically significant improvement in overall survival with one year of adjuvant olaparib compared to placebo. The trial demonstrated the value of precision medicine in an early setting.^1,10

In spite of all the advances in the treatment of breast cancer, there have been very few adjuvant treatments in breast cancer that have led to improvement in overall survival, so this was a major milestone for patients.^11-14

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4 years after OlympiAD, results from the OlympiA trial led to the 2022 approval of LYNPARZA for patients with BRCA1/2 mutation-associated early-stage breast cancer. This represented a major treatment advance. We are able to use this targeted therapy to treat more patients. In the early-stage setting, drugs that improve overall survival, have such a tremendous impact on natural course of the disease.^20,21

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Based on this subsequent approval, further refinements were made in recommendations for genetic testing, paving the way to where we are today. While there is some variability among guidelines, recommendations include testing for all patients with metastatic breast cancer. In early-stage setting, recommendations include testing for patients with triple negative breast cancer and for patients with hormone positive breast cancer if they meet the risk criteria for adjuvant LYNPARZA based on the OlympiaA eligibility. It’s not just based on family history, but if patients with hormone positive breast cancer meet the criteria in terms of the number of positive nodes or amount of residual disease after preoperative chemotherapy, they are candidates for gBRCA testing. Regardless of family history, these individuals should be tested to ensure that we are not missing an opportunity to prescribe a targeted treatment that improves survival.^8,22

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In my clinical practice, LYNPARZA is fairly well tolerated. It’s got nausea, fatigue, impact on hemoglobin and blood counts.¹

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The field continues to move forward, and we look for better treatments for our patients. There are some phase 2 trials that have looked at PARP inhibitors in the neoadjuvant setting as a chemotherapy free regimen and shown interesting results. It’s not something we currently use in clinic, but it’s an area of expanding research.^23,24

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In general, my experience with LYNPARZA in clinic has been very positive. It is a very tolerable oral drug for our patients. And it’s quite efficacious in appropriately selected patients.

In other cancers, specifically ovarian and prostate, the indications are wider than just germline BRCA mutation. In breast cancer, the data from phase 2 trials in patients with somatic BRCA mutations looks quite promising.^1,25

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I would like to share a case of a patient who was treated with LYNPARZA. A 56-year-old woman was diagnosed with pT2N2 HR+, HER2- breast cancer. She underwent a bilateral mastectomy with reconstruction and received adjuvant AC-T followed by 5 years of aromatase inhibitor therapy. Her family history was significant only for her mother who had ovarian cancer, but there was no family history of breast cancer.

Two years after stopping adjuvant AI therapy, she developed osseous metastasis and two small pulmonary nodules. She was treated with first line endocrine therapy with AI plus a CDK46 inhibitor, which resulted in disease control for 2.5 years. At that point, she began to show progression in osseous disease and developed malignant pleural effusion. Her care was transferred to a new institution, where they performed germline testing, which showed that she had a pathogenic germline BRCA2 mutation.

The patient was started on then recently approved LYNPARZA for her metastatic breast cancer and had disease control for 2 years. She experienced mild nausea, which was managed with antiemetics. 4 months after starting LYNPARZA, her hemoglobin dropped to 6.6 but she showed no signs or symptoms of bleeding. LYNPARZA was paused for 3 weeks until her hemoglobin count rose to >10, and LYNPARZA was started at one dose level reduction, which the patient was able to tolerate for the rest of her therapy for another year when eventually there was progression of the cancer.

Cascade testing was performed for her family and showed one of her two daughters also had a germline BRCA2 mutation. Clearly the genetic testing information was helpful not just for the patient for also very informative for her family.

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In terms of where I see LYNPARZA headed in the future, the first aspect is expanding the use of germline BRCA testing to all appropriate patients. While in academic clinics, we often do well with proactive testing for patients with triple negative breast cancer, there are many missed opportunities in patients with metastatic disease and HR+ early-stage patients who don’t receive BRCA testing.

Additionally, oncologists are time strapped and may not have access to the required resources and infrastructure to offer/refer for genetic testing. Historically, genetic testing when only used for cancer risk counseling was done by genetic counselors, which limits access for many patients who may not be able to get an appointment with a genetic counselor in a timely fashion, don’t have access to counselors or have to wait weeks to get tested, or simply just fall through the cracks because they are too overwhelmed with cancer diagnosis and could not get to yet another appointment with a provider. In patients with breast cancer BRCA testing’s main purpose is to inform treatment of cancer and an easier process which is not burdensome for patients is desirable.

Many practices now have a point-of-care testing initiated by treating providers (eg by oncologist, surgeons, physician extenders) to expedite the testing and to make the process easy for the patients. Efforts are being made to integrate genetic testing into routine oncology workflow; however, a lot more work needs to be to be done to improve testing rates.²⁶

Most patients with metastatic breast cancer are getting somatic tumor or ctDNA testing, which could pick up germline mutations but requires germline testing to confirm. It is to be noted that somatic tumor/ctDNA testing can also miss germline mutations so are not a good way to screen for germline mutations.²⁷

As stated earlier, for early-stage disease, the oncology community is doing okay in terms of genetic testing for patients with triple negative breast cancer. However, in hormone receptor-positive disease, eligible patients might be missed if they’re older and don’t have family history of breast cancer or don’t have a record of family history.

The literature suggests that a quarter or more eligible patients are still not getting germline tested, and it varies based on type of practice and the healthcare setting. For example, in marginalized communities, access to resources is more challenging. Due to these disparities in healthcare access, minorities, individuals living in rural communities, and those from lower socioeconomic demographics are getting tested less. Through improved infrastructure and access to resources, oncologists and support teams could be better empowered to discuss genetic testing. Note that oncology providers are ordering somatic testing on a routine basis to aid in treatment decision making.^28,29

While LYNPARZA may already be helping many patients with certain breast cancers, improving genetic testing rates in breast cancer patients will help to identify more patients who are eligible for targeted therapy with LYNPARZA.

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In the context of current approval, genetic BRCA1/2 testing is recommended for all patients with metastatic breast cancer, among patients with early stage disease for all patients with TNBC regardless of age of diagnosis of cancer or family history, for patients with HER2 negative breast cancer who may be eligible of adjuvant LYNPARZA again regardless of family history, and for others who might meet criterion based on age of diagnosis or family history.²²

In terms of where we should be headed outside of current approval, I think there’s a lot of scientific questions that would fall under research.

I look forward to seeing how LYNPARZA can continue to expand across different treatment settings and across different tumor types.

1. LYNPARZA^® (olaparib) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2023.
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25. Tung NM, Robson ME, Ventz S, et al. TBCRC 048: Phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. J Clin Oncol. 2020;38:4274-4282.
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