The U.S Food and Drug Administration has approved olaparib (Lynparza®; AstraZeneca and Merck & Co) for the adjuvant treatment of patients with germline BRCA-mutated (gBRCAm) HER2-negative high-risk early breast cancer who have already been treated with chemotherapy either before or after surgery.

Olaparib is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumors harboring a deficiency in homologous recombination repair (HRR), such as those with mutations in BRCA1 and/or BRCA2, or those where deficiency is induced by other agents (such as new hormonal agents – NHAs).

Professor Andrew Tutt, Ph.D., FRCR, MRCP, MB, ChB, Global Chair of the OlympiA Phase III trial and Professor of Oncology at The Institute of Cancer Research, London and King’s College London, UK.

The approval was based on results from the OlympiA Phase III trial.  These results were presented during the 2021 American Society of Clinical Oncology Annual Meeting and were simultaniously published in The New England Journal of Medicine (NEJM).[1]

In the trial, olaparib demonstrated a statistically significant and clinically meaningful improvement in invasive disease-free survival (iDFS), reducing the risk of invasive breast cancer recurrences, second cancers or death, by 42% versus placebo (based on a hazard ratio [HR] of 0.58; 95% confidence interval [CI] 0.46-0.74; p<0.0001).

New updated results from the OlympiA trial also showed olaparib demonstrated a statistically significant and clinically meaningful improvement in the key secondary endpoint of overall survival (OS), reducing the risk of death by 32% versus placebo (based on a HR of 0.68; 95% CI 0.50-0.91; p=0.0091).

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The safety and tolerability profile of LYNPARZA in this trial was in line with that observed in prior clinical trials. The OS data will be presented at an upcoming European Society for Medical Oncology (ESMO) virtual plenary on March 16, 2022, which are freely available to all healthcare professionals working in Oncology.

Breast cancer is the most diagnosed cancer worldwide with an estimated 2.3 million patients diagnosed in 2020.[2] Almost 91% of all breast cancer patients in the US are diagnosed at an early stage of disease and BRCA mutations are found in approximately 5-10% of patients.[3][4]

“Today’s approval of olaparib is great news for patients with a specific inherited form of breast cancer. Most breast cancers are identified in the early stages and many patients will do very well, but for those with higher risk disease at diagnosis, the risk of cancer returning can be unacceptably high and new treatment options are needed,” noted Professor Andrew Tutt, Ph.D., FRCR, MRCP, MB, ChB, Global Chair of the OlympiA Phase III trial and Professor of Oncology at The Institute of Cancer Research, London and King’s College London, in London, United Kingdom.

“The OlympiA trail has shown that identifying a BRCA1/2 mutation in women with high risk disease opens the additional option of eligibility for olaparib treatment, which reduces the risk of recurrence and improves survival for these breast cancer patients,” Tutt added.

A new targeted therapy option
“This important approval gives early-stage breast cancer patients in the US with a germline BRCA mutation a new targeted therapy option in the adjuvant setting starting today,” noted Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca.

“Olaparib reduces the risk of disease recurrence in these high-risk patients and now new data confirm it also significantly extends patients’ lives versus placebo. These data underline the importance of germline BRCA testing as soon as possible after diagnosis to identify patients that may be eligible for olaparib,” Fredrickson explained.

Living longer
“For patients with germline BRCA-mutated, HER2-negative high-risk early breast cancer, who often present with more aggressive disease, today’s approval is an important step forward,” said Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, Merck Research Laboratories.

“Compared to placebo, olaparib as adjuvant treatment offers these patients the potential to live longer without their cancer recurring. We thank the patients, caregivers and healthcare providers for their participation in the OlympiA trial,” Baynes concluded.

BRCA 1 and BRCA2
BRCA1 and BRCA2 are human genes that produce proteins responsible for repairing damaged DNA and play an important role maintaining the genetic stability of cells.[5]
When either of these genes is mutated or altered such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly, and cells become unstable. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer and confer sensitivity to PARP inhibitors including olaparib.[5][6][7][8]

Olaparib is now indicated for the adjuvant treatment of adult patients with deleterious or suspected deleterious gBRCAm HER2-negative high-risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy. Patients are to be selected for treatment based on results from the BRACAnalysis® CDx test (Myriad Genetics), an FDA-approved companion diagnostic test for olaparib.

“Studies have demonstrated that PARP inhibitors are highly effective in patients with BRCA1/BRCA2 mutations. Once we identify these patients, they will have more options for treatment,” explained Thomas Slavin, M.D., chief medical officer, Myriad Genetics.

“This important advancement underscores the need for breast cancer patients being evaluated for approved therapies to know their BRCA status with an FDA-approved test right after diagnosis to help ensure they will receive the best available therapy. Additionally, the quick adoption of OlympiA criteria by guideline committees greatly supports the advancement of genomics in clinical care.”

The BRACAnalysis companion diagnostic test classifies a patient’s clinically significant variants (DNA sequence variations) in the germline BRCA1and BRCA2 genes. Variants are classified into one of the five categories; “Deleterious,” “Suspected Deleterious,” “Variant of Uncertain Significance,” “Favor Polymorphism,” or “Polymorphism.” Once the classification is completed, the results identify patients with germline BRCA-mutated (gRBCAm) HER2 negative, high-risk early-stage breast cancer who may benefit from (olaparib).  Following this identification, these results are are then used for determining the eligibility of patients for treatment with olaparib.

Strategic oncology collaboration
Olaparib, which is being jointly developed and commercialized by AstraZeneca and Merck, is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

July 2017, AstraZeneca and Merck & Co., announced a global strategic oncology collaboration to co-develop and co-commercialize olaparib, the world’s first PARP inhibitor, and selumetinib, a mitogen-activated protein kinase (MEK) inhibitor, for multiple cancer types.

Working together, the companies develop olaparib and selumetinib in combination with other potential new medicines and as monotherapies. The companies also develop olaparib and selumetinib in combination with their respective PD-L1 and PD-1 medicines independently.

Olaparib is approved in the US, EU, Japan and several other countries for the treatment of patients with gBRCAm, HER2-negative, metastatic breast cancer previously treated with chemotherapy based on results from the OlympiAD Phase III trial. In the EU, this indication also includes patients with locally advanced breast cancer.

Clinical trials
Olaparib as Adjuvant Treatment in Patients with Germline BRCA Mutated High Risk HER2 Negative Primary Breast Cancer (OlympiA) – NCT02032823

Highlights of prescribing information
Olaparib (Lynparza®; AstraZeneca and Merck & Co) (Prescribing Information)

[1] Tutt ANJ, et al. Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer. N Engl J Med 2021;384:2394-2405.
[2] Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians. 2020;0:1-41.
[3] American Cancer Society. Breast Cancer Facts & Figures 2019-2020. Online. Last accessed March 11, 2022.
[4] Early-stage breast cancer. Online. Last accessed on March 11, 2022
[5] Roy R, et al. BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer. 2016;12(1):68-78.
[6] Wu J, et al. The role of BRCA1 in DNA damage response. Protein Cell 2010;1(2):117-123.
[7] Gorodetska I, et al. BRCA Genes: The Role in Genome Stability, Cancer Stemness and Therapy Resistance. Journal of Cancer. 2019;10:2109-2127.
[8] Li H, et al. PARP inhibitor resistance: the underlying mechanisms and clinical implications. Molecular Cancer. 2020;19:1-16.

Featured image: Laboratories at AstraZeneca. Photo Courtesy: © 2020 – 2022 AstraZeneca. Used with permission

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