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Study Finds Side Effects of Experimental Buparlisib Too Toxic

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Buparlisib is an experimental targeted therapy medicine that inhibits the PI3K pathway. The PI3K pathway helps all cells -- both healthy and cancer cells -- get the energy they need. When this pathway is mutated or overactivated, it can allow cancer cells to survive and grow. When hormone-receptor-positive cancers become resistant to hormonal therapy, this pathway becomes overactivated. PI3K inhibitors block this pathway, with the goal of killing cancer cells, as well as making hormone-receptor-positive cancers start responding to hormonal therapy again.

So researchers hypothesized that women diagnosed with advanced-stage, hormone-receptor-positive breast cancer that had stopped responding to hormonal therapy could be treated with buparlisib, which would make the cancer start responding to hormonal therapy again, instead of chemotherapy.

A study called the BELLE-3 trial found that buparlisib combined with the hormonal therapy medicine Faslodex (chemical name: fulvestrant) offered benefits to postmenopausal women diagnosed with hormone-receptor-positive, HER2-negative, advanced-stage breast cancer that had previously been treated with an aromatase inhibitor and had grown after being treated with Afinitor (chemical name: everolimus).

Still, while buparlisib increased the time until the cancer grew, the side effects, including mood disorders and suicide attempts, were too severe. It is unlikely that research on buparlisib will move forward.

The study was presented on Dec. 8, 2016 at the 2016 San Antonio Breast Cancer Symposium.

Read the abstract of “BELLE-3: A phase III study of buparlisib + fulvestrant in postmenopausal women with HR+, HER2-, aromatase inhibitor-treated, locally advanced or metastatic breast cancer, who progressed on or after mTOR inhibitor-based treatment.”

The BELLE-3 trial included 432 postmenopausal women diagnosed with advanced-stage, hormone-receptor-positive, HER-negative breast cancer that previously had been treated with an aromatase inhibitor for hormonal therapy. All the cancers had grown while the women were being treated with Afinitor.

The women were randomly assigned to one of two treatments:

  • buparlisib and Faslodex (289 women)
  • placebo (a pill that looked just like buparlisib but didn’t contain any medicine) and Faslodex (143 women)

The characteristics of the women in the study:

  • they ranged in age from 32 to 84
  • 65% of them had three or more sites of metastatic disease (cancer that had spread to parts of the body away from the breast area, such as the liver or bones)
  • 35% had been treated with chemotherapy for metastatic disease
  • 69% had been treated with at least two types of hormonal therapy for metastatic disease, though none had been treated with Faslodex before

Women who had a history of mood disorders were not allowed to participate in the study.

The researchers found that compared to Faslodex alone, buparlisib improved progression-free survival by 2.1 months:

  • progression-free survival was 3.9 months for women treated with buparlisib and Faslodex
  • progression-free survival was 1.8 months for women treated with Faslodex alone

Progression-free survival is how long the women lived 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.

After 6 months, 31% of the women treated with buparlisib and Faslodex had no cancer growth compared to 20% of the women treated with Faslodex alone.

“Buparlisib improved progression-free survival by a couple of months, but the problem is it was quite toxic,” said Ruth O’Regan, M.D., professor of hematology and oncology at the University of Wisconsin and one of the study authors. “The most serious side effect is it gets into the brain and causes anxiety and depression. It also causes elevation of liver function enzymes, which is another concern.”

Even though women with a history of mood disorders were not allowed to participate in the study, the effects of buparlisib were so severe that a few patients attempted suicide while taking buparlisib.

“So even though the study shows us that there is a signal there and that by inhibiting this pathway, it does appear to be beneficial for patients to some degree, the toxicity’s a problem with this drug,” Dr. O’Regan added.

Two other ongoing studies are looking at different experimental PI3K pathway inhibitors in combination with hormonal therapy in postmenopausal women or men diagnosed with advanced-stage, hormone-receptor-positive, HER2-negative breast cancer that grew after treatment with an aromatase inhibitor. The SOLAR-1 study is studying alpelisib in combination with Faslodex and the SANDPIPER study is looking at taselisib in combination with Faslodex. Both studies are currently recruiting participants.

If you’re being treated for advanced-stage, hormone-receptor-positive, HER2-negative breast cancer that has stopped responding to an aromatase inhibitor, you and your doctor may be considering a number of treatment options. If you’re willing to participate in a clinical trial, you may have even more options, possibly including an experimental treatment such as a PI3K pathway inhibitor. Talk to your doctor about clinical trials that might be a good fit for you and your unique situation. Visit the Clinical Trials pages for more information.

And stay tuned to for more news about how PI3K pathway inhibitors are being used to treat advanced-stage breast cancer.

Listen to a podcast with Dr. Ruth O’Regan about her research on buparlisib.

Editor’s Note: On May 24, 2019, the U.S. Food and Drug Administration approved Piqray (chemical name: alpelisib) in combination with Faslodex to treat metastatic and advanced-stage, hormone-receptor-positive, HER2-negative breast cancer with a PIK3CA mutation that has grown after hormonal therapy treatment in postmenopausal women and men.

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