Lynparza (olaparib) is an oral treatment developed by AstraZeneca in collaboration with Merck (known as Merck in the U.S. and Canada, but as MSD everywhere else) for advanced ovarian, pancreatic and certain types of metastatic breast cancer.
The U.S. Food and Drug Administration (FDA) approved Lynparza in January 2018 for treating patients with germ-line mutations in the BRCA 1 and BRCA2 genes who have locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative breast cancer. The European Commission (EC) followed suit in April 2019. Patients must have been treated previously with, or be considered unsuitable, for chemotherapy. Patients with hormone receptor (HR)-positive breast cancer should have progressed after treatment with hormonal therapy, or be considered unsuitable for endocrine treatment.
How Lynparza works
DNA carries genetic information in both healthy and cancer cells. DNA is prone to damage through several mechanisms. If DNA damage is not repaired, cells may accumulate deleterious mutations that can have one of two consequences: cells not being able to sustain themselves and dying, or cells surviving despite mutations that can transform them into cancer cells. There are several DNA repair mechanisms that operate in cells to rectify different types of DNA damage.
The protein products of two related genes, BRCA1 and BRCA2, are critical for the survival and normal function of breast cancer cells. Mutations in these two genes are generally associated with most of the inherited cases of breast cancers because both these genes are involved in DNA repair. Subsequently, breast cancer cells with BRCA1/2 mutations adapt and become reliant on other DNA repair mechanisms such as the PARP (poly ADP-ribose polymerase) enzyme, which repairs single-strand DNA breaks.
Lynparza inhibits the PARP enzyme, which makes it harder for the breast cancer cells that already lack BRCA1 and BRCA2 to repair their damaged DNA. Treatment with Lynparza will sensitize the breast cancer cells and cause their death.
Lynparza in clinical trials
Lynparza has been approved by the FDA and the EC based on the results of a Phase 3 placebo-controlled study (NCT02000622), which compared the safety and effectiveness of Lynparza to that of standard chemotherapy. The results of this study were published in the Journal of Clinical Oncology.
This study, called OlympiAD, included 302 women with germline BRCA1– and/or BRCA2-mutated, HER2-negative (HR-positive or triple-negative) breast cancer. Among these, 205 were randomized to receive Lynparza at a dose of 300 mg twice daily and 97 were randomized to receive standard chemotherapy such as Xeloda (capecitabine), Navelbine (vinorelbine), or Halaven (eribulin).
Patients treated with Lynparza showed a statistically-significant median progression-free survival improvement of 2.8 months (7 months for Lynparza versus 4.2 months for chemotherapy). The objective response rate (ORR) in patients treated with Lynparza was twice compared to those undergoing standard chemotherapy (52% for Lynparza versus 23% for standard chemotherapy). Lynparza also showed fewer side effects compared to standard chemotherapy (36.6% versus 50.5%). The rate of discontinued treatment due to toxicity in the Lynparza group was 4.9% compared to 7.7% in the chemotherapy group.
A randomized, double-blind, placebo-controlled, multi-center Phase 3 study (NCT02032823) called OlympiA has recruited 1,819 participants to assess the effectiveness and safety of Lynparza in patients with germline BRCA1/2 mutations and high-risk HER2 negative primary breast cancer. The patients must have completed definitive local treatment and neoadjuvant or adjuvant chemotherapy. They are being randomized in a 1:1 ratio to either Lynparza or placebo. The randomization will be further classified based on the hormone receptor status of the tumor, prior neoadjuvant versus adjuvant chemotherapy, and prior platinum use. Patients will receive treatment for 12 months and will be clinically assessed during and after treatment for 10 years. After this, the patients will enter into the survival follow up phase of the study. The primary phase of this study is expected to be completed in November 2020 and the entire study is expected to be completed in November 2028.
Another randomized, Phase 2/3 clinical trial (NCT03150576) called PARTNER is enrolling about 527 participants in the U.K. to evaluate the safety and effectiveness of concurrent platinum-based chemotherapy compared to Lynparza in breast cancer patients with triple-negative breast cancer and/or germline BRCA1/2 mutated breast cancer. The study is expected to be completed in January 2032.
There are at least 30 other clinical trials currently recruiting participants to study the effect of Lynparza in breast cancer patients under several contexts such as in combination with other treatments, or studying its effects on different subtypes of breast cancer.
For example, a Phase 2 randomized trial (NCT03598257) is recruiting about 300 participants to assess whether radiation therapy together with Lynparza may work better in treating patients with inflammatory breast cancer than radiation therapy alone.
Another Phase 2 international, multi-center, open-label, single-arm, Phase 2 study (NCT03367689) called NOBROLA is recruiting 39 participants in Spain to analyze the safety and effectiveness of monotherapy with Lynparza in non-BRCA-mutated metastatic breast cancer patients.
A Phase 1b/2 study (NCT03641755) is recruiting 64 participants in the Boston, Massachusetts area to analyze whether a combination of Lynparza and Sapacitabine is more effective in the treatment of BRCA-mutant breast cancer than when used alone.
Other information
The FDA also approved Lynparza as monotherapy in patients with germ-line BRCA-mutated metastatic ovarian cancer who have been treated with three or more prior lines of chemotherapy. The treatment also is approved by the European Medicines Agency (EMA) as a monotherapy to treat patients with platinum-sensitive, relapsed, BRCA-mutated, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer that respond to platinum-based chemotherapy.
The most common adverse side effects caused by Lynparza are anemia, nausea, fatigue, vomiting, diarrhea, loss of sense of taste, indigestion, headache, decreased appetite, cough, rash, and pain in the muscles, bones, back, and abdomen.
Last updated: 07/11/2019
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