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Lynparza Better Than Standard Chemotherapy for HER2-Negative Metastatic Breast Cancer in Women With BRCA Mutations

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A study found that Lynparza (chemical name: olaparib) improved progression-free survival by about 3 months in women diagnosed with metastatic, HER2-negative breast cancer who had a BRCA1 or BRCA2 mutation.

Progression-free survival is how long a woman lives without the cancer growing.

The research was published online on June 4, 2017 by The New England Journal of Medicine. Read the abstract of “Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation.”

Most inherited cases of breast cancer are associated with mutations in two genes: BRCA1 (BReast CAncer gene one) and BRCA2 (BReast CAncer gene two). Women with a BRCA1 or BRCA2 genetic mutation have up to a 72% risk of developing breast cancer by age 80. Their risk of ovarian cancer also is higher than average. Men with an abnormal BRCA gene have a higher risk of both breast and prostate cancer.

DNA carries genetic information in both healthy cells and cancer cells. Cells can develop DNA damage spontaneously or from exposure to specific things in the environment (too much sun, for example) that make DNA damage more likely to happen. But cells can detect and repair damage to DNA. When DNA is damaged in a healthy cell and the damage isn't fixed, that cell can become cancerous. Abnormal BRCA1 and BRCA2 genes are thought to increase the risk of breast and other cancers because these abnormal genes interfere with cells' ability to repair damaged DNA.

The poly ADP-ribose polymerase (PARP) enzyme fixes DNA damage in both healthy and cancer cells. Researchers believe that a medicine like Lynparza, which interferes with (inhibits) the PARP enzyme, might make it even harder for cancer cells with an abnormal BRCA1 or BRCA2 gene to fix DNA damage. This would make it harder for the cancer cells to survive. In other words, a PARP inhibitor might make some cancer cells less likely to survive their DNA damage.

Lynparza is a pill taken by mouth.

Research in the lab on cancer cells with an abnormal BRCA1 or BRCA2 gene showed that the cells were 1,000 times more sensitive to PARP inhibition than cancer cells that didn’t have an abnormal BRCA gene. Based on those results, the researchers felt that treating cancers in people with an abnormal BRCA1 or BRCA2 gene with Lynparza would probably be effective.

In this study, called the OlympiAD trial, 302 women with a known BRCA1 or BRCA2 mutation who had been diagnosed with metastatic, HER2-negative breast cancer were randomly assigned to get one of two treatments:

  • Lynparza alone (one 300 mg tablet twice a day) -- 205 women
  • standard chemotherapy treatment with either Xeloda (chemical name: capecitabine), Halaven (chemical name: eribulin), or Navelbine (chemical name: vinorelbine); the chemotherapy medicine was chosen by the women’s doctors -- 97 women

The women received the treatments until the cancer grew or unacceptable side effects developed:

  • about half the women were older than 45 and half were younger
  • about half the cancers were hormone-receptor-positive and half were triple-negative
  • more than 70% of the women had been treated with chemotherapy for metastatic disease before

The researchers looked to see how long the women lived without the cancer growing, as well as how many of the cancers responded to Lynparza.

Overall, women treated with Lynparza lived longer without the cancer growing than women treated with standard chemotherapy:

  • women in the Lynparza group lived about 7.0 months without the cancer growing
  • women in the standard chemotherapy group lived about 4.2 months without the cancer growing

This difference was statistically significant, which means that it was likely because of the difference in treatment and not just due to chance.

"This is the first phase III study to show an advantage of a PARP inhibitor over standard-of-care chemotherapy in breast cancer patients with a BRCA mutation," said Mark Robson, M.D., of Memorial Sloan Kettering Cancer Center who was the lead author of the study. "It is our opinion that olaparib could be an effective treatment option for women with BRCA mutations and metastatic HER2-negative breast cancer, including, importantly, women with BRCA mutations in triple-negative disease."

The cancers also responded better to Lynparza:

  • 59.9% of the cancers in the Lynparza group had some response to the treatment
  • 36.6% of the cancers in the standard chemotherapy group had some response to the treatment

Lynparza also caused fewer serious side effects than the standard chemotherapy treatment:

  • 36.6% of women in the Lynparza group had a serious side effect; 4.9% of the women stopped treatment because of side effects
  • 50.5% of women in the standard chemotherapy group had a serious side effect; 7.7% of the women stopped treatment because of side effects

"There were fewer grade 3 and 4 toxicities in the olaparib group, and there was an improvement in overall quality of life in the olaparib group," said Susan Domchek, M.D., executive director of the Basser Research Center for BRCA at the University of Pennsylvania's Abramson Cancer Center and one of the study’s authors. "The response rate was twice as high in the olaparib group compared with chemotherapy. All in all, everything's pointing in a really positive direction with this drug."

In the United States, Lynparza currently is approved to treat advanced-stage ovarian cancer in women with a BRCA1 or BRCA2 mutation who have been treated with three or more prior lines of chemotherapy.

If you have a BRCA1 or BRCA2 gene mutation and are being treated for metastatic, HER2-negative breast cancer, you and your doctor may be considering a number of treatment options. If the cancer has stopped responding to standard treatments, other treatment options may include a PARP inhibitor such as Lynparza if you’re willing to participate in a clinical trial. Ask your doctor if there are any clinical trials that might be a good fit for you and your unique situation. Visit the Clinical Trials pages for more information.

Editor’s Note: On Jan. 12, 2018, Lynparza (chemical name: olaparib) was approved by the U.S. Food and Drug Administration to treat metastatic HER2-negative breast cancer in women with a BRCA1 or BRCA2 mutation that has been previously treated with chemotherapy.

Editor’s Note: This article was updated on Jan. 24, 2019, with updated information on cancer risk associated with BRCA mutations.

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