FDA Approves Olaparib for BRCA-Mutated Patients with Heavily Pretreated Advanced Ovarian Cancer

Companion diagnostic test also approved to detect the presence of BRCA mutations

On 19 December, 2014 the USA Food and Drug Administration (FDA) granted accelerated approval to olaparib (Lynparza), a new drug treatment for women with heavily pretreated advanced ovarian cancer that is associated with defective BRCA genes, as detected by an FDA-approved test.

Olaparib is a poly ADP-ribose polymerase (PARP) inhibitor that blocks enzymes involved in repairing damaged DNA.

“Today’s approval constitutes the first of a new class of drugs for treating ovarian cancer,” said Dr Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Lynparza is approved for patients with specific abnormalities in the BRCA gene and is an example of how a greater understanding of the underlying mechanisms of disease can lead to targeted, more personalized treatment.”

The FDA approved olaparib with a genetic test called BRACAnalysis CDx, a companion diagnostic that will detect the presence of mutations in the BRCA genes (gBRCAm) in blood samples from patients with ovarian cancer. The BRCA genes are involved with repairing damaged DNA and normally work to suppress tumour growth. Women with mutations resulting in defective BRCA genes are more likely to get ovarian cancer, and it is estimated that 10% to 15% of all ovarian cancer is associated with these hereditary BRCA mutations.

The FDA evaluated the BRACAnalysis CDx’s safety and efficacy under the agency’s premarket approval pathway used for high-risk medical devices. Until now, the manufacturer, a clinical laboratory, had been marketing this test, although not specifically for use as a companion diagnostic, without FDA approval as a laboratory developed test (LDT), which is a test that is designed, manufactured and used in a single laboratory. The new test is approved as a companion diagnostic, specifically to identify patients with advanced ovarian cancer who may be candidates for treatment with olaparib.

“The approval of safe and effective companion diagnostic tests and drugs continue to be important developments in oncology,” said Alberto Gutierrez, PhD, director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health. “We are very excited that the BRACAnalysis CDx is the FDA’s first approval of an LDT under a premarket approval application and is the first approval of an LDT companion diagnostic. The use of companion diagnostics helps bring to market safe and effective treatments specific to a patient’s needs.”

The FDA’s approval of the BRACAnalysis CDx is based on data from the clinical study used to support approval of olaparib. Blood samples from clinical trial participants were tested to validate the test’s use for detecting BRCA mutations in this population.

Olaparib’s efficacy was examined in a study where 137 participants with gBRCAm-associated ovarian cancer received the drug. The study was designed to measure objective response rate (ORR), or the percentage of participants who experienced partial shrinkage or complete disappearance of the tumour. Results showed 34% of participants experienced ORR for an average of 7.9 months.

Common side effects of olaparib included nausea, fatigue, vomiting, diarrhoea, dysgeusia, dyspepsia, headache, decreased appetite, nasopharyngitis, cough, arthralgia, musculoskeletal pain, myalgia, back pain, dermatitis and abdominal pain. Serious side effects included the development of myelodysplastic syndrome, acute myeloid leukaemia, and lung inflammation.

The most common laboratory abnormalities were increased creatinine, red blood cells’ mean corpuscular volume elevation, decreased haemoglobin, decreased lymphocytes and neutrophils, and decreased platelet levels.

In June, olaparib was reviewed by the FDA’s Oncologic Drugs Advisory Committee for potential use as maintenance therapy. The committee advised the agency in a vote of 11 to 2 that the data did not support olaparib’s accelerated approval for this use. After the meeting, the company submitted additional information supporting olaparib’s use for a different use: in patients with gBRCAm-associated ovarian cancer who have received three or more chemotherapy treatments.

The FDA is approving olaparib under the agency’s accelerated approval programme, which allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients. This programme provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials. Olaparib’s application was reviewed under the FDA’s priority review programme, which provides for an expedited review of drugs that are intended to treat a serious disease or condition and, if approved, would offer significant improvement compared to marketed products.

BRACAnalysis CDx’s application was reviewed under the FDA’s priority review programme for devices, which provides for priority review of devices that meet certain criteria, including that the devices are intended to treat or diagnose a life-threatening or irreversibly debilitating disease or condition and, if approved, would offer significant, clinically meaningful advantages compared to marketed products.

Lynparza is marketed by AstraZeneca Pharmaceuticals, based in Wilmington, Delaware. BRACAnalysis CDx is manufactured by and performed at Salt Lake City, Utah-based Myriad Genetic Laboratories, Inc.