FDA Approves Olaparib (Lynparza) for BRCA Ovarian Cancer

Zosia Chustecka


December 19, 2014

The first-in-class drug olaparib (Lynparza, AstraZeneca) has been approved in the United States for the treatment of advanced ovarian cancer with BRCA mutations.

This comes as a surprise, as earlier this year at meeting of the Oncologic Drugs Advisory Committee (ODAC) of the US Food and Drug Administration (FDA), panel members voted against the approval of olaparib.

The FDA explains its move in a press release announcing the approval. The ODAC meeting held earlier this year had considered a different use of the drug, as a maintenance therapy, to prevent ovarian cancer recurrence (on the basis of data from a placebo-controlled trial in 136 patients with platinum-sensitive ovarian cancer [Lancet Oncol. 2014;15:852-861]). As reported at the time by Medscape Medical News, the panel had voted 11 to 2 against recommending accelerated approval for this use.

However, after the meeting, the manufacturer submitted additional data supporting a different use for olaparib, specifically its use in patients with BRCA-mutated ovarian cancer who have already received three or more chemotherapy treatments. These data came from a single-group open-label trial in 137 patients with BRCA-mutated ovarian cancer (J Clin Oncol. Published online November 3, 2014).

The FDA granted an accelerated approval for this use of the drug, after an expedited review process, for products that are intended to treat a serious disease or condition that, if approved, would offer significant improvement compared with those already on the market.

Olaparib was approved for a similar indication in the European Union just yesterday, but that approval had been expected, as it had received a recommendation for approval in October from the European Medicines Agency.

First-in-Class PARP Inhibitor

Olaparib is the first in a class of drugs that inhibit poly(ADP)-ribose polymerase (PARP), and it is indicated for use in heavily pretreated women with advanced ovarian cancer with BRCA mutations, as detected by an FDA-approved test.

"Today's approval constitutes the first of a new class of drug for treating ovarian cancer," said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research. "Olaparib 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."

Companion Diagnostic Test Also Approved

The genetic test for identifying women who are suitable for treatment with olaparib is BRACAnalysis CDx (Myriad), a companion diagnostic that will detect the presence of BRCA mutations in blood samples from patients with ovarian cancer, the FDA noted.

The BRCA genes are involved with repairing damaged DNA and normally work to suppress tumor 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 agency noted.

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, Myriad, had been marketing this test, although not specifically for use as a companion diagnostic, without FDA approval as a laboratory developed test, which is a test that is designed, manufactured, and used in a single laboratory. Now the test is approved as a companion diagnostic, specifically to identify patients with advanced ovarian cancer who may be candidates for treatment with olaparib, the agency noted in its press release.

"We believe [this test] opens a new door in personalized medicine and represents a big step forward in tailoring treatment for women with ovarian cancer," said Mark Capone, president, Myriad Genetic Laboratories. "Less than 25% of ovarian cancer patients know their germline BRCA status, which is critical for any ovarian cancer patient who may be considered for treatment with olaparib."


Clinical Trial Data

The approval of the companion diagnostic test was made on the basis of the open-label trial in 137 patients with BRCA-mutated ovarian cancer, all of whom received olaparib, the FDA noted. The approval of olaparib was also based on this study, with additional data considered also from other studies.

Blood samples from clinical trial participants were tested to validate the test's use for detecting BRCA mutations in this population, the agency said.

The study was designed to measure objective response rate (ORR), or the percentage of participants who experienced partial shrinkage or complete disappearance of the tumor. Results showed 34% of participants experienced ORR for an average of 7.9 months.

Common adverse effects of olaparib included nausea, fatigue, vomiting, diarrhea, distorted taste (dysgeusia), dyspepsia, headache, decreased appetite, nasopharyngitis, cough, arthralgia, musculoskeletal pain, myalgia, back pain, dermatitis, and abdominal pain.

Serious adverse effects included the development of myelodysplastic syndrome, acute myeloid leukemia (a bone marrow cancer), and lung inflammation, the FDA noted.

The most common laboratory abnormalities were increased creatinine, increased mean corpuscular volume elevation, decreased red blood cell count, decreased white blood cell count, and decreased platelet levels.

More Studies Underway

For the current accelerated approval to be converted to a full approval, the manufacturer needs to submit data from the ongoing SOLO phase 3 clinical trial.

Two other phase 3 trials are underway: the SOLO2 trial is evaluating olaparib compared with placebo as a maintenance therapy (results expected in 2015), and the SOLO3 trial is evaluating olaparib compared with standard chemotherapy for relapsed disease (results expected in 2019).


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