FDA Approval of Olaparib for Certain Breast Cancers

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Highlights:

• The US FDA has endorsed olaparib suitable to treat certain breast cancers that have spread to other parts of the body and have a specific inherited gene mutation (mutated-BRCA).
• Olaparib is currently used to treat advanced ovarian cancers due to an inherited BRCA gene mutation.
• In a recent clinical trial in BRCA positive metastatic breast cancer, olaparib provided a more safe and effective treatment option than standard chemotherapy.

The U.S. Food and Drug Administration (FDA) has approved the expansion of the indications of the anti-cancer drug olaparib. Olaparib can now be used to treat patients with certain breast cancers that have spread and where the tumors are caused by a specifically inherited genetic mutation called BRCA mutation. Olaparib is the first drug in its class, a PARP protein inhibitor, to be approved to treat breast cancer and specifically for such an indication.

Olaparib has been specifically indicated for abnormal inherited (germline) breast cancer susceptibility (BRCA) gene, human epidermal growth factor receptor 2 (HER2)-negative breast cancer that has spread to other parts of the body (metastatic).

‘Olaparib has shown promise as an anti-cancer therapy in patients with HER-2 negative metastatic breast cancer and a germline BRCA mutation.’

These patients should have received anti-cancer or chemotherapy drugs, either before or after cancer has spread. If the patients have hormone receptor (HR)-positive breast cancer then they should have either been treated with a prior hormonal (endocrine) therapy or be considered inappropriate for endocrine treatment.

Patients have to undergo an FDA-approved genetic test called the BRACAnalysis CDx to be eligible for treatment with olaparib. To suit the current new indication, the FDA has also expanded the approval of the BRACAnalysis CDx to include detection of BRCA mutations in blood samples from patients with breast cancer.

The approval follows the positive results of the Phase 3 OlympiAD Clinical Trial that evaluated the efficacy and safety of olaparib:

Patients (302 in number) with HER2-negative metastatic breast cancer with an inherited BRCA mutation and who had received one or two previous chemotherapy regimens were eligible for the clinical trial. They were randomly assigned (in a ratio of 2:1) to receive olaparib tablets (300 mg twice daily) or standard therapy (capecitabine, eribulin, or vinorelbine in 21-day cycles).

The primary endpoint of the study was progression-free survival or PFS which is the length of time after the treatment that the tumors do not grow significantly or do not get worse.

Results of the Study

• The median PFS was significantly longer (7 months in the olaparib group) compared to 4.2 months for patients in the standard-therapy group.
• Patients in the olaparib group had a better response rate (59.9%) compared with 28.8% in the standard-therapy group.
• Olaparib also proved to be a safer treatment option (the rates of grade 3 or higher adverse events was 36.6% with olaparib, compared with 50.5% standard therapy drugs). In addition, lesser patients had to discontinue due to the toxic effects olaparib during the trial.
• Based on this study, it appears that olaparib provides a safer and more effective treatment option than standard chemotherapy for patients with HER2-negative metastatic breast cancer and an inherited BRCA mutation.

Additional studies are also being done - assessing olaparib as maintenance therapy after platinum-based treatment of breast cancer, and studying PARP inhibitors in combination with immune checkpoint inhibitors.

In the US, olaparib is already in the market for the treatment of women who have advanced ovarian cancer due to a certain type of mutated inherited BRCA gene and who have also received three or more prior lines of chemotherapy. Other indications for which olaparib is prescribed are epithelial ovarian, fallopian tube or primary peritoneal cancers that have recurred.

"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," said Richard Pazdur, M.D., 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."

About PARP and BRCA

DNA or deoxyribose nucleic acid contains the genetic instructions used by most living organisms to grow, develop, function and reproduce. It is thus a vital substance found in all the cells of the body. By nature, one strand or both strands of DNA can break or get damaged and when that happens, the DNA undergoes a repair mechanism.

Both PARP and BRCA are proteins that are involved in repairing damaged DNA. PARP or poly (ADP-ribose) polymerase proteins are enzymes that repair DNA when one strand breaks.

BRCA proteins repair DNA when both strands break. Thus, BRCA genes normally work to prevent tumor development. When BRCA genes get mutated (mutated-BRCA), the respective proteins function abnormally and errors occur in the DNA repair. This may lead to certain cancers, including breast cancers.

Olaparib, being a PARP inhibitor, works by inhibiting the activity of PARP enzymes, in other words, stalls the repair of damaged DNA.

With the BRCA genes already mutated in cancerous cells, blocking PARP enzyme further prevents DNA repair, resulting in a buildup of damaged DNA, leading to cell death and possibly a slow-down or stoppage of tumor growth.

About Breast Cancer

Breast cancer is cancer that starts in the breast tissue. It is the most common form of cancer in women, affecting 1 in 8 women. It can affect men too. BRCA1 and BRCA2 genes are two different genes (BRCA is BReast CAncer gene) which when mutated can increase the risk of female breast and ovarian cancers. Around 20-25 percent of patients with hereditary breast cancers have a BRCA mutation in their genes.

References:

1. FDA approves first treatment for breast cancer with a certain inherited genetic mutation - (https:www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm592347.htm)
2. Mark Robson, M.D., Seock-Ah Im, M.D., Ph.D., El bieta Senkus, M.D., Ph.D., Binghe Xu, M.D., Ph.D., Susan M. Domchek, M.D., Norikazu Masuda, M.D., Ph.D., Suzette Delaloge, M.D., Wei Li, M.D., Nadine Tung, M.D., Anne Armstrong, M.D., Ph.D., Wenting Wu, Ph.D., Carsten Goessl, M.D., Sarah Runswick, Ph.D., and Pierfranco Conte, M.D. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med 2017; 377:523-533August 10, 2017 DOI: 10.1056/NEJMoa1706450

Source: Medindia

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