AstraZeneca and Merck & Co., Inc., (Merck: known as MSD outside the US and Canada) announced that the US Food and Drug Administration (FDA) has approved Lynparza (olaparib), for use in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have been previously treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor positive (HR+) breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Patients are selected for therapy based on an FDA-approved companion diagnostic from Myriad Genetics.

Dave Fredrickson, executive vice president, head of the oncology business unit, AstraZeneca, said: “This new approval for Lynparza makes it the first and only PARP inhibitor approved in metastatic breast cancer, and the only PARP inhibitor approved beyond ovarian cancer. This is significant for breast cancer patients, as the identification of BRCA status, in addition to hormone receptor and HER2 status, becomes a potentially critical step in the management of their disease.”

Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories said: “This additional approval for Lynparza represents an important advance for women with HER2-negative metastatic breast cancer with a germline BRCA mutation, which is a difficult-to-treat cancer. Moreover, this approval adds further impetus to our important collaboration with AstraZeneca in developing cancer therapies.”

The approval was based on data from the randomised, open-label, Phase III OlympiAD trial which investigated Lynparza versus physician’s choice of chemotherapy (capecitabine, eribulin, or vinorelbine). In the trial, Lynparza significantly prolonged progression-free survival (PFS) compared with chemotherapy, and reduced the risk of disease progression or death by 42% (HR 0.58; 95% CI 0.43-0.80; P=0.0009 median 7.0 vs 4.2 months). Patients with measurable disease taking Lynparza (n=167) experienced an objective response rate of 52% (95% CI 44-60), double the response rate for those in the chemotherapy arm (n=66) which was 23% (95% CI 13-35). Additionally, patients experienced a confirmed complete response rate of 7.8% for Lynparza compared to 1.5% for the chemotherapy arm. The data from the OlympiAD trial can be found in the June 2017 issue of the New England Journal of Medicine.

Susan M. Domchek, executive director of the Basser Center for BRCA at the Abramson Cancer Center of the University of Pennsylvania, and a national leader on the OlympiAD trials, said: “Patients diagnosed with BRCA-related metastatic breast cancer are often younger than other breast cancer patients, and their disease is often much more aggressive and difficult to treat. While there is currently no cure for metastatic breast cancer, today’s approval offers a new, targeted option that may help to delay disease progression for these patients.”

The most common adverse reactions (=20%) in the OlympiAD trial of patients who received Lynparza were nausea (58%), anaemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhoea (21%), and headache (20%). The percentage of patients who discontinued treatment in the Lynparza arm was 5% compared to the chemotherapy arm which was 8%.

This is the third indication approved for Lynparza in the US, where it has been used to treat nearly 4,000 advanced ovarian cancer patients. Lynparza has the broadest clinical development programme of any PARP inhibitor, and AstraZeneca and MSD are working together to deliver Lynparza as quickly as possible to more patients across multiple settings, including breast, ovarian, prostate and pancreatic cancers.

Under the oncology collaboration with Merck, announced in July 2017, AstraZeneca is potentially eligible for more than $6 billion of future Sustainable and Ongoing Externalisation Revenue in the form of sales-related and approval-related payments in addition to option payments until 2019. Following this new approval for Lynparza, AstraZeneca will receive $70 million in Sustainable and Ongoing Externalisation Revenue.

OlympiAD is a randomised, open-label, multicentre Phase III trial assessing the efficacy and safety of Lynparza tablets (300 mg twice daily) compared to physician’s choice of chemotherapy in 302 patients with HER2-negative metastatic breast cancer with germline BRCA1 or BRCA2 mutations, which are confirmed or suspected to be deleterious. The international trial was conducted in 19 countries across Europe, Asia, North America and South America.

Patients in the OlympiAD trial had HER2-negative gBRCA1- or gBRCA2-mutated breast cancer, which was HR+ or triple negative, and received Lynparza for metastatic disease. Approximately half of the patients in the Lynparza and chemotherapy arm of the trial were HR+ (n=152), and approximately half were triple negative (n=150). Among the 205 patients treated with Lynparza, the median age was 44 years (range: 22 to 76). Before enrolment, patients had prior treatment with an anthracycline (unless contraindicated) and a taxane chemotherapy either in the neoadjuvant, adjuvant or metastatic setting and no more than two prior lines of chemotherapy for metastatic disease. Hormone receptor-positive patients had received at least one endocrine medicine or were not eligible for endocrine medicines. Prior treatments with endocrine medicines were not counted as prior lines of chemotherapy.

The primary endpoint of the trial was PFS as measured by a Blinded Independent Central Review. Secondary endpoints included overall survival, time to second progression or death, objective response rate, and effect on health-related quality of life.

Lynparza is the first FDA-approved oral poly ADP-ribose polymerase (PARP) inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. Specifically, in vitro studies have shown that Lynparza-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.

Lynparza is being investigated in a range of DDR-deficient tumour types and is the foundation of AstraZeneca’s industry-leading portfolio of compounds targeting DDR mechanisms in cancer cells.

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the United States and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the world’s first PARP inhibitor, and potential new medicine selumetinib, a MEK inhibitor, for multiple cancer types. The collaboration is based on increasing evidence that PARP and MEK inhibitors can be combined with PD-L1/PD-1 inhibitors for a range of tumour types. Working together, the companies will develop Lynparza and selumetinib in combination with other potential new medicines and as a monotherapy. Independently, the companies will develop Lynparza and selumetinib in combination with their respective PD-L1 and PD-1 medicines.