by Dr. C.H. Weaver M.D. updated 5/2022
The US Food and Drug Administration (FDA) has approved Lynparza (olaparib) for treatment of metastatic breast cancer and women with earlier stage high-risk breast cancers who carry an inherited BRCA mutation. Adjuvant Lynparza led to a 32% reduction in the risk of disease progression or death and improved overall survival compared with placebo.
Lynparza belongs to a class of precision cancer medicines known as "PARP" inhibitors. Lynparza and other PARP inhibitors were developed to treat BRCA mutated ovarian cancer and are increasingly used to treat other BRCA mutated cancers including breast, prostate and pancreatic cancer.1-8
All patients with breast cancer should be evaluated for the BRCA 1 and 2 genes which can be identified by using the FDA-approved genetic test, BRACAnalysis CDx (Myriad Genetic Laboratories).
About BRCA-mutated Breast Cancer
Breast cancer is the most common type of cancer in women, with some 250,000 individuals diagnosed in the U.S. this year. BRCA1/2 are human genes that produce proteins involved in DNA repair. When either of these genes is altered or mutated, DNA repair may not progress correctly. This can lead to the development of certain types of cancer such as breast cancer. BRCA mutations can be hereditary (germline) or occur spontaneously (somatic). Together, BRCA1 and BRCA2 mutations account for about 25 to 30% of hereditary breast cancers and about 5 to 10% of all breast cancers.
About PARP Inhibitors
The poly ADP-ribose polymerase (PARP) enzyme plays a role in DNA repair, including the repair of DNA damage from chemotherapy. PARP inhibitors target and inhibit this enzyme and may contribute to cancer cell death and increased sensitivity to chemotherapy. By blocking this enzyme, DNA inside the cancerous cells is less likely to be repaired, leading to cell death and possibly a slow-down or stoppage of tumor growth.
Lynparza in High-Risk Early-Stage HER2-Negative Breast Cancer & BRCA 1/2 Mutations
The addition of 1 year of treatment with the PARP inhibitor Lynparza after completion of standard neoadjuvant or adjuvant chemotherapy, surgery and radiation significantly delays cancer progression and improves survival in patients with BRCA1/2 germline mutations in high-risk early-stage breast cancer that is negative for human epidermal growth factor receptor 2 (HER2).6
In the OlympiA clinical trial 1,836 patients with germline BRCA1 or BRCA2 mutations and high-risk early-stage breast cancer that was negative for over expression of HER2 were treated with Lynparza or no additional therapy after standard adjuvant treatment and directly compared. All participants had already received standard adjuvant or neoadjuvant chemotherapy, surgery and radiation therapy if needed for early-stage breast cancer disease.
Patients treated with Lynparza experienced improved cancer free and overall survival. Three years from treatment 86% of lynparza treated patients survived cancer free compared to 77% for individuals not receiving the PARP inhibitor.8
Patients treated with PARP inhibitors have a small but serious risk of developing myelodysplasia and acute myeloid leukemia-this should be discussed with the treating physician.
What is 'High-Risk"?
High risk disease was defined as the presence of axillary involvement or a tumor greater than 2 cm for TNBC or at least 4 positive lymph nodes, or the absence of a pathologic complete response (pCR) following neoadjuvant chemotherapy for hormone receptor positive, HER2 negative (HR+/HER2-) breast cancer.
The trial results highlight the need for testing for BRCA mutations in patients diagnosed with high-risk early-stage breast cancer. These results could have an important impact on treatment decisions for this patient population, possibly including the use of a PARP inhibitor in the adjuvant setting.
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Lynparza in BRCA-mutated HER 2 Negative Advanced Breast Cancer
The safety and effectiveness of Lynparza in the treatment of advanced breast cancer were determined on the basis of findings from the OlympyiAD clinical trial, a randomized clinical trial of 302 patients with HER2-negative metastatic breast cancer with a germline BRCA mutation. In the OlympyiAD clinical study in women whose breast cancer had spread, Lynparza reduced the risk of cancer growing by 42% compared to treatment with chemotherapy. Overall 60% of the patients who received Lynparza experienced a response compared to only 29% of those treated with chemotherapy. The time to cancer progression was delayed almost twice as long for Lynparza treated patients compared to those receiving chemotherapy.
This was the first comparative clinical trial in breast cancer that shows PARP inhibitors are superior to chemotherapy for HER2-negative metastatic breast cancer patients who have a BRCA mutation. Interim results in a real-world population of patients with HER2-negative metastatic breast cancer with germline BRCA mutations were published at ASCO 2020 and were consistent with the OlympiAD study, supporting Lynparza as a chemotherapy-free alternative treatment for patients with advanced breast cancer with germline BRCA mutations.3
The FDA has approved 2 PARP inhibitors, Lynparza, and Talzenna (talazoparib) for treatment of certain patients with HER2-negative breast cancer.
The EMBRACA clinical trial directly compared Talzeenna to chemotherapy in 431 patients with an inherited BRCA1/2 mutation and locally advanced or metastatic triple negative or hormone receptor-positive (HR+)/HER2- breast cancer. Talazoparib delayed the time to cancer recurrence and prolonged survival compared to chemotherapy
Veliparib in BRCA-mutated Metastatic Breast Cancer
The addition of the PARP inhibitor veliparib to carboplatin and paclitaxel chemotherapy significantly delays cancer progression for patients with metastatic breast cancer who have germline BRCA mutations.2
In a clinical study 509 previously treated patients with germline BRCA1- or BRCA2-mutated metastatic breast cancer received treatment with carboplatin and paclitaxel chemotherapy with or without the PARP inhibitor veliparib and were directly compared.
Analyses of the women treated with or without veliparib performed a median of about 3 years after beginning treatment showed that at 2 years survival without cancer progression was 33.6% with and 25.7% without veliparib. The benefit persisted at 3 years with 19.8% of veliparib treated patients surviving cancer free compared to 10.7% of those treated with chemotherapy alone.
The treatment regimen was well-tolerated and it did not compromise the administration of chemotherapy and the most common significant side effects with the veliparib regimen were anemia, neutropenia and thrombocytopenia.4,5
- Robson M., Im SA., Senkus E., et al, OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm), Presented at the American Society of Clinical Oncology Annual Meeting, Chicago; June 2-6, 2017.
- Dieras VC, et al. Abstract LBA9. Presented at: European Society for Medical Oncology Congress; Sept. 27-Oct. 1, 2019; Barcelona, Spain.
- Gelmon KA, Fasching PA, Couch F, et al. Real-world clinical effectiveness and safety of olaparib monotherapy in HER2-negative gBRCA-mutated metastatic breast cancer: Phase IIIb LUCY interim analysis. Presented at: the 2020 ASCO Annual Meeting; May 29-31, 2020. Abstract 1087.
- Diéras V, et al "Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): A randomized, double-blind, placebo-controlled phase III trial" Lancet Oncol 2020; DOI: 10.1016/S1470-2045(20)30447-2
- Telli M, et al "BROCADE3: A challenge to the treatment paradigm in BRCA breast cancer?" Lancet Oncol 2020; DOI: 10.1016/S1470-2045(20)30431-9.
- ClinicalTrials.gov. Olaparib as Adjuvant Treatment in Patients with Germline BRCA Mutated High Risk HER2 Negative Primary Breast Cancer (OlympiA). Available at . Accessed February 2021.
- Tutt ANJ, Garber J, Gelber RD, Gelber K-A, Phillips A, Eisen OT, et al. Pre-specified event driven analysis of Overall Survival (OS) in the OlympiA phase III trial of adjuvant olaparib (OL) in germline BRCA1/2 mutation (gBRCAm) associated breast cancer. ESMO Virtual plenary session. 2022; March 16.;VP1-2022.