For the first time, a drug is indicated specifically for BRCA-mutated breast cancer.
The US Food and Drug Administration (FDA) has extended the approval of olaparib (Lynparza, AstraZeneca/Merck & Co) to include the treatment of metastatic breast cancer in patients who carry the specific inherited BRCA mutation.
These patients can be identified by using the FDA-approved genetic test, BRACAnalysis CDx (Myriad Genetic Laboratories).
About 10% to 15% of patients with any type of breast cancer have a BRCA mutation, the agency notes.
Olaparib acts as an inhibitor of the enzyme poly-(ADP-ribose) polymerase (PARP), which is involved in the repair of damaged DNA, it explains.
By blocking this enzyme, DNA inside the cancerous cells with damaged BRCA genes may be less likely to be repaired, leading to cell death and possibly a slowdown or stoppage of tumor growth.
Olaparib is already approved for use in germline BRCA-mutated ovarian cancer. The initial approval, granted in 2014, was for use in BRCA-mutated advanced ovarian cancer in patients who have received three or more treatments of chemotherapy. Earlier this year, the FDA granted approval for maintenance use in patients with recurrent epithelial ovarian, fallopian tube cancer, or primary peritoneal cancer whose tumors have completely or partially responded to chemotherapy.
In addition to olaparib, another PARP inhibitor has been approved for use in BRCA ovarian cancer ― rucaparib (Rubraca, Clovis Oncology). A third PARP inhibitor, niraparib (Zejula, Tesaro), is approved for use in ovarian cancer irrespective of whether or not the patients carries a BRCA mutation.
Olapraib becomes the first PARP inhibitor to be approved for use in breast cancer.
"This class of drugs has been used to treat advanced BRCA-mutated ovarian cancer and has now shown efficacy in treating certain types of BRCA-mutated breast cancer," commented Richard Pazdur, MD, director of the FDA's Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research.
"This approval demonstrates the current paradigm of developing drugs that target the underlying genetic causes of a cancer, often across cancer types," he added.
Clinical Trial Data
The agency notes that the safety and efficacy of olaparib in the treatment of breast cancer were determined on the basis of findings from the OlympyiAD trial, a randomized clinical trial of 302 patients with HER2-negative metastatic breast cancer with a germline BRCA mutation.
The OlympyiAD trial was presented at this year's annual meeting of the American Society of Oncology, as reported at the time by Medscape Medical News.
In this trial, patients were assigned to receive either olaparib 300 mg twice daily (n = 205) or standard therapy (n = 92), which consisted of 21-day cycles of capecitabine (2500 mg/m2 orally on days 1 to 14) or vinorelbine (30 mg/m2 intravenously on days 1 and 8) or eribulin (1.4 mg/m2 intravenously on days 1 and 8).
At the time of the primary analysis (median follow-up of 14 months), overall survival did not differ significantly between the two treatment arms: 94 patients (45.9%) in the olaparib group and 46 patients (47.4%) in the chemotherapy group had died. The median time to death was 19.3 months for patients who received olaparib and 19.6 months for those who received standard therapy.
But the difference in progression-free survival (PFS) was significant: the median PFS was 7.0 months with olaparib vs 4.2 months with chemotherapy (hazard ratio, 0.58; P = .0009).
The objective response rate also favored olaparib, at 59.9% vs 28.8%.
"This is the first phase 3 randomized trial in breast cancer that shows PARP inhibitors are superior to chemotherapy for HER2-negative metastatic breast cancer patients who have a BRCA mutation," said lead study author Mark E. Robson, MD, clinic director of the Clinical Genetics Service and medical oncologist at Memorial Sloan Kettering Cancer Center in New York City.
"This study is proof of the principle that breast cancers with defects in a specific DNA damage-repair pathway are sensitive to a targeted therapy designed to exploit that defect," said Dr Robson.
Olaparib was generally well tolerated, with fewer than 5% of the cohort discontinuing treatment because of toxicity, he added.
The FDA notes that common side effects of olaparib include anemia, neutropenia, leukopenia, nausea, fatigue, vomiting, nasopharyngitis, respiratory tract infection, influenza, diarrhea, arthralgia/myalgia, dysgeusia, headache, dyspepsia, decreased appetite, constipation, inflammation, and stomatitis.
Severe side effects include development of myelodysplastic syndrome/acute myeloid leukemia and pneumonitis. It is potentially fetotoxic, so women should use effective contraception and should not breastfeed while taking the drug.
Cite this: First Drug for BRCA Breast Cancer: Olaparib - Medscape - Jan 12, 2018.