CDK4/6 Inhibitor Plus Aromatase Inhibitor Helps Treat Breast Cancer, No Matter a Woman’s Age

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An analysis of three studies on different CDK4/6 inhibitors in combination with an aromatase inhibitor to treat postmenopausal women diagnosed with metastatic, hormone-receptor-positive, HER2-negative breast cancer found the treatment combination was effective in both younger and older women. Still, women older than 75 had more side effects and were more likely to have to decrease the dose of the medicine.

The study was published online on Sept. 27, 2019, by the Journal of Clinical Oncology. Read the abstract of “Outcomes of Older Women With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor-Negative Metastatic Breast Cancer Treated With a CDK4/6 Inhibitor and an Aromatase Inhibitor: An FDA Pooled Analysis.”

Metastatic breast cancer is cancer that has spread to parts of the body away from the breast, such as the bones or liver.

About CDK4/6 inhibitors and aromatase inhibitors

Ibrance (chemical name: palbociclib), Kisqali (chemical name: ribociclib), and Verzenio (chemical name: abemaciclib) are all cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. A kinase is a type of protein in the body that helps control cell division. CDK4/6 inhibitors work by stopping cancer cells from dividing and growing.

All three CDK4/6 inhibitors are pills taken by mouth.

Aromatase inhibitors are a type of hormonal therapy used to treat hormone-receptor-positive breast cancer. Aromatase inhibitors stop the production of estrogen in postmenopausal women. Aromatase inhibitors work by blocking the enzyme aromatase, which turns the hormone androgen into small amounts of estrogen in the body. This means that less estrogen is available to stimulate the growth of hormone-receptor-positive breast cancer cells.

There are three aromatase inhibitors:

  • Arimidex (chemical name: anastrozole)
  • Aromasin (chemical name: exemestane)
  • Femara (chemical name: letrozole)

Each is a pill, usually taken once a day. All three are available as generic medicines.

While the three CDK4/6 inhibitors are used in similar ways, there are some differences between them:

  • Ibrance is used in combination with an aromatase inhibitor to treat advanced-stage or metastatic, hormone-receptor-positive, HER2-negative breast cancer that hasn’t been treated with hormonal therapy before in postmenopausal women or men. Ibrance also is approved to be used in combination with the hormonal therapy Faslodex (chemical name: fulvestrant) to treat advanced-stage or metastatic, hormone-receptor-positive, HER2-negative breast cancer that has grown after being treated with hormonal therapy in postmenopausal women or men.
  • Kisqali is used in combination with an aromatase inhibitor to treat advanced-stage or metastatic hormone-receptor-positive, HER2-negative breast cancer that hasn’t been treated with hormonal therapy yet in premenopausal, perimenopausal, and postmenopausal women. Premenopausal and perimenopausal women treated with Kisqali also should be treated with a luteinizing hormone-releasing hormone agonist, such as Zoladex (chemical name: goserelin), to suppress ovarian function. Kisqali also is used in combination with Faslodex to treat advanced-stage or metastatic, hormone-receptor-positive, HER2-negative breast cancer that hasn’t been treated with hormonal therapy yet, or has grown while being treated with a different hormonal therapy, in postmenopausal women.
  • Verzenio is used in combination with an aromatase inhibitor as the first hormonal therapy to treat advanced-stage or metastatic, hormone-receptor-positive, HER2-negative breast cancer in postmenopausal women. Verzenio also is used in combination with Faslodex to treat women diagnosed with hormone-receptor-positive, HER2-negative, metastatic or advanced-stage breast cancer if the cancer grew after hormonal therapy treatment. Verzenio is used alone to treat women and men diagnosed with hormone-receptor-positive, HER2-negative, metastatic or advanced-stage breast cancer if the cancer grew after hormonal therapy treatment and earlier chemotherapy for metastatic disease.

About the study

Research shows that 75% to 80% of breast cancers diagnosed in women older than 65 are hormone-receptor-positive and HER2-negative. Research also shows that people age 65 and older make up only about 21% of people in breast cancer clinical trials. Since many older women will be treated with a CDK4/6 inhibitor and an aromatase inhibitor, the researchers wanted to see if the combination was as effective in older women as it is in younger women.

To do the analysis, the researchers looked at information from three studies on CDK4/6 inhibitors:

  • PALOMA-2, which looked at Ibrance and Femara
  • MONALEESA-2, which looked at Kisqali and Femara
  • MONARCH 3, which looked at Verzenio and Arimidex or Femara

All three studies looked to see if the combination of a CDK4/6 inhibitor and an aromatase inhibitor offered better progression-free survival than the aromatase inhibitor alone in women diagnosed with metastatic, hormone-receptor-positive, HER2-negative breast cancer.

Progression-free survival is how long the women lived without the cancer growing.

Overall, the studies included 1,827 women:

  • 456 women were age 70 or older
  • 198 women were age 75 or older

Progression-free survival in women age 75 and older was:

  • 31.1 months for women treated with a CDK4/6 inhibitor and an aromatase inhibitor
  • 13.7 months for women treated with only an aromatase inhibitor

Progression free-survival in women age 70 and older was:

  • 33.1 months for women treated with a CDK4/6 inhibitor and an aromatase inhibitor
  • 19.2 months for women treated with only an aromatase inhibitor

Progression-free survival in women younger than 70 was:

  • 27.3 months for women treated with a CDK4/6 inhibitor and an aromatase inhibitor
  • 14.1 months for women treated with only an aromatase inhibitor

The analysis shows that the combination of a CDK4/6 inhibitor and an aromatase inhibitor works just as well in older women as it does in younger women.

Side effects

The researchers also wanted to know if older women had more or more severe side effects from the combination of a CDK4/6 inhibitor and an aromatase inhibitor compared to younger women. They found:

  • Older women were more likely to have a severe side effect compared to younger women; 88.8% of women age 75 and older had a severe side effected compared to 73.4% of women younger than 75.
  • Side effects leading to a reduction in the dose of the CDK4/6 inhibitor or stopping treatment were more common in older women; 81.6% of women age 75 and older had a dose reduction compared to 71.1% of women younger than 75, and 32% of women age 75 and older stopped treatment compared to 12.1% of women younger than 75.

The most common side effects leading to a dose reduction or stopping treatment were:

  • neutropenia (low white blood cell counts)
  • diarrhea
  • kidney problems

“As CDK4/6 inhibitors are incorporated into the standard of care for the initial treatment of [hormone-receptor-positive], HER2-negative, [metastatic breast cancer], this pooled analysis provides important efficacy, safety, and tolerability data for counseling older women who are considering use of aromatase inhibitors in combination with CDK4/6 inhibitors,” the researchers concluded. “Compared with their younger counterparts, older patients derived similar benefit from treatment with a CDK4/6 inhibitor [and] worsened toxicity that could be managed with supportive care…”

What this means for you

If you’re an older woman who has been diagnosed with metastatic, hormone-receptor-positive, HER2-negative breast cancer and are considering treatment with a CDK4/6 inhibitor and an aromatase inhibitor, this study offers reassuring results.

If you’re concerned about side effects, it makes sense to talk to your doctor about them. You may want to ask how you will be monitored for side effects and which treatments are available to ease them.

For more information on CDK4/6 inhibitors, visit the Breastcancer.org pages on Targeted Therapies.

Written by: Jamie DePolo, senior editor

Reviewed by: Brian Wojciechowski, M.D., medical adviser


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