comscoreExperimental Talazoparib Seems Better Than Chemotherapy for Metastatic HER2-Negative Disease in Women With a BRCA Mutation

Experimental Talazoparib Seems Better Than Chemotherapy for Metastatic HER2-Negative Disease in Women With a BRCA Mutation

The targeted therapy talazoparib resulted in longer progression-free survival compared to chemotherapy in women with a BRCA1 or BRCA2 mutation diagnosed with metastatic HER2-negative breast cancer.
Dec 20, 2017.This article is archived
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A study found that treatment with talazoparib, an experimental targeted therapy medicine, resulted in longer progression-free survival than chemotherapy in women with a BRCA1 or BRCA2 mutation diagnosed with metastatic HER2-negative breast cancer.
Progression-free survival is how long the women lived without the cancer growing.
Many 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 talazoparib, 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.
Talazoparib is a pill taken by mouth once per day.
“Talazoparib is a PARP inhibitor, and it actually blocks one of the enzymes that helps DNA repair itself,” explained Dr. Jennifer Litton, associate professor of breast medical oncology at the University of Texas MD Anderson Cancer Center, who presented the research. “And in addition to blocking that repair, it also sits and traps itself onto the DNA strand while [the DNA is] trying to divide. So it stops these cells that are rapidly dividing from dividing, and the cell dies off.”
The U.S. Food and Drug Administration (FDA) has approved three PARP inhibitors so far:
  • Lynparza (chemical name: olaparib)
  • Rubraca (chemical name: rucaparib)
  • Zejula (chemical name: niraparib)
to treat certain types of ovarian cancer, including ovarian cancers with BRCA mutations.
This study, called the EMBRACA trial, included 431 women with a known BRCA1 or BRCA2 mutation who had been diagnosed with metastatic HER2-negative breast cancer:
  • half the women were older than 46 and half were younger
  • 54% of the breast cancers were hormone-receptor-positive
  • 45% of the women had a BRCA1 mutation
  • 55% of the women had a BRCA2 mutation
  • 38% of the women had not been treated with chemotherapy for the metastatic breast cancer
  • 15% of the women had metastatic breast cancer that had spread to the brain
The women were randomly assigned in a 2:1 ratio to one of two treatment groups:
  • 287 women were treated with talazoparib
  • 144 women were treated with their doctor’s choice of chemotherapy
The chemotherapy medicines used in the study were:
  • Xeloda (chemical name: capecitabine)
  • Halaven (chemical name: eribulin)
  • Gemzar (chemical name: gemcitabine)
  • Navelbine (chemical name: vinorelbine)
The women were treated with either talazoparib or chemotherapy until they developed unacceptable side effects or the cancer grew.
At the time of this interim analysis, the women had been followed for about 11 months.
The researchers found that women who were treated with talazoparib had longer progression-free survival than women treated with chemotherapy. Progression-free survival was:
  • 8.6 months for women treated with talazoparib
  • 5.6 months for women treated with chemotherapy
This difference was statistically significant, which means that it was likely due to the difference in treatment and not just because of chance.
The results also showed that more cancers responded to talazoparib than to chemotherapy:
  • 62.6% of cancers treated with talazoparib had some response to the treatment
  • 27.2% of cancers treated with chemotherapy had some response to the treatment
This difference also was statistically significant.
Women treated with talazoparib also had better quality of life than women treated with chemotherapy. Women treated with talazoparib lived for more than 2 years before their health started to deteriorate, while women treated with chemotherapy experienced health deterioration about 6 months after starting chemotherapy.
“Importantly, the trial met its primary endpoint of progression-free survival,” Litton said. “Patients were nearly 46% less likely to have progressed on talazoparib compared to physician's choice. Secondary endpoints also were promising, including a dramatic improvement in time to clinical deterioration among patients receiving talazoparib."
The researchers also will look at whether talazoparib improves overall survival compared to chemotherapy. Overall survival is how long the women live, whether or not the cancer grows. Because this is an interim analysis, the data were not mature enough to analyze overall survival. Still, Litton said that there was a positive trend toward talazoparib.
“At the time that we were doing this analysis, there was a preplanned analysis to look at overall survival if the progression-free survival was positive,” she explained. “So we did take a look at overall survival, but please know that it is an interim analysis, and only 51% of the events needed to calculate this were observed at this time. The hazard ratio, 0.76, it is not statistically significant at this time. But the interesting thing is when we look at the curves, the curves are really separating at the end of the tail of the curves. As we look now, there is a significantly higher percentage of patients still on talazoparib or still being followed for survival, compared to the physician’s choice. So I think following this out as these data mature is going to be very important.”
Like most cancer medicines, talazoparib can cause side effects, some of them severe. About 55% of the women treated with talazoparib and 39% of the women treated with chemotherapy had severe blood cell count side effects. For women treated with talazoparib, the severe side effects were mostly anemia (low red blood cell counts). For women treated with chemotherapy, the severe side effects were mostly neutropenia (low white blood cell counts).
“We are seeing an increase of anemia in patients with talazoparib, often very well managed with either dose delays or dose reductions,” Litton said. “Some patients did need blood transfusions; however, only two patients in the entire study needed to come off talazoparib because of anemia.”
Hair loss was another side effect of talazoparib. While the percentage of women who experienced hair loss was about the same in the two treatment groups, women treated with talazoparib had milder hair loss than women treated with chemotherapy.
"The trial found that talazoparib provides a significant clinical benefit to all patient subgroups, including those with hormone-receptor-positive and triple-negative disease," Litton added. "The results of this trial are quite exciting and indicate talazoparib is a novel treatment option for patients with metastatic breast cancer and BRCA mutations."
The EMBRACA trial was a phase III trial. Because the results are encouraging, it’s expected that Pfizer, the company that makes talazoparib, will apply for FDA approval. Still, it’s not clear when this will happen.
If you have an abnormal BRCA1 or BRCA2 gene 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 talazoparib 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.
Listen to a podcast with Dr. Litton about the EMBRACA trial.
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.

— Last updated on February 22, 2022, 10:01 PM

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