CDK 4/6 Inhibitors May Be Effective but More Toxic in Older Women

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OLDER WOMEN with breast cancer derive benefit from treatment with cyclin-dependent kinase (CDK) 4/6 inhibitors as part of initial endocrine-based therapy for hormone receptor–positive, HER2-negative, metastatic breast cancer, according to a retrospective pooled subgroup analysis of women aged 70 or older enrolled in registration trials of these agents.1 However, these data are just a few years old, and longer-term data are needed. 

Harpreet Singh, MD

Harpreet Singh, MD

“Our large analysis suggests older women derive the same benefits as younger women from treatment with CDK 4/6 inhibitors as part of endocrine therapy,” said lead author Harpreet Singh, MD, of the Office of Hematology and Oncology Products at the U.S. Food and Drug Administration. 

“Accrual of older women to clinical trials is challenging, and they are underrepresented in clinical trials,” Dr. Singh explained. Women aged 75 and older comprise about 4% of the population of breast cancer clinical trials but account for 19% of all new cases of breast cancer each year. More than 40% of breast cancer–related deaths occur in women aged 70 or older.1,2 

CDK 4/6 inhibitors are now indicated as part of initial endocrine-based therapy for hormone receptor–positive, HER2-negative, advanced or metastatic breast cancer and for disease progression following endocrine therapy, yet there are limited data on the safety and efficacy of these agents in older women. 

“There appears to be a similar benefit of treatment with CDK 4/6 inhibitors no matter what the patient’s age.”
— Harpreet Singh, MD

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Study Details 

AT THE 2017 San Antonio Breast Cancer Symposium, Dr. Singh presented the results of a pooled retrospective subgroup analysis designed to determine the efficacy of CDK 4/6 inhibitors in older women with hormone receptor–positive, HER2-negative, advanced or metastatic breast cancer.3 The efficacy population included 716 women younger than age 65, 555 women aged 65 or older, of whom 329 women were aged 70 or older. Efficacy was determined according to progression-free survival in treated and control groups according to age. 

The vast majority of women in all three age groups had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Bone-only metastatic disease was present in 22% to 29%; visceral disease was present in 43% to 49%. Of those older than age 65, about 40% had prior neoadjuvant endocrine therapy and about 50% had stage IV disease. 


FOR PATIENTS older than age 70 treated with CDK 4/6 inhibitors, median progression-free survival was not reached. For those younger than age 70 who received CDK 4/6 inhibitors, median progression-free survival was 23.75 months. Median progression-free survival for patients treated with an aromatase inhibitor alone was 16.8 months for those older than age 70 and 13.8 months for those younger than age 70. 

“There appears to be a similar benefit of treatment with CDK 4/6 inhibitors no matter what the patient’s age,” Dr. Singh told listeners. 

Safety and Tolerability 

SAFETY WAS assessed in all patients who received at least one dose of CDK 4/6 inhibitor therapy. Twenty-five percent were older than age 70; 43% were 65 years or older, and 57% were younger than age 65. 


  • CDK 4/6 inhibitors added to endocrine therapy provide a progression-free survival benefit for older patients equivalent to that in younger patients.
  • A trend toward more serious side effects in older women was observed.
  • Longer-term data are needed, as are data on patients who are less fit with more comorbidities than those included in clinical trials.

The rates of grades 1 and 2 adverse events were similar across all three age groups. However, higher rates of grades 3 and 4 adverse events were observed in both older age groups compared with younger patients. 

The rates of adverse events leading to dose reduction or interruption were higher in older patients, as were the rates of treatment discontinuation. Serious adverse events were reported in 33% of those older than age 70, 31% of those older than age 65, and 16% of those younger than age 65. As for selected adverse events, the rates of neutropenia and hepatotoxicity were similar among all age groups, whereas an upward trend for infections, diarrhea, and fatigue was observed among older patients. 

Study limitations included the fact that it was a pooled analysis of three different CDK 4/6 inhibitors with similar but distinct safety profiles and that there were few patients older than age 75. 

“Older patients enrolled in clinical trials are not representative of those seen in clinical practice. They are often more fit with a better performance status. Perhaps patients should be characterized according to assessment of physical fitness rather than chronologic age,” Dr. Singh suggested. 

“To improve accrual of older patients, eligibility criteria for clinical trials should be revisited for older patients,” she suggested. “We need to become more adept at obtaining real-world data to help answer important clinical questions about our older patients with cancer. Patient-reported outcomes will also provide more data on how patients experience these agents.” ■

DISCLOSURE: Dr. Singh reported no conflicts of interest. 


1. Siegel RL, Miller KD, Jemal A: Cancer statistics, 2016. CA Cancer J Clin 66:7-30, 2016

2. Breast Cancer Facts & Figures 2107-2018. American Cancer Society. Available at Accessed January 29, 2018. 

3. Singh H, Howie LJ, Bloomquist E, et al: A U.S. Food and Drug Administration pooled analysis of outcomes of older women with hormone receptor-positive metastatic breast cancer treated with a CDK4/6 inhibitor as initial endocrine therapy. 2017 Annual San Antonio Breast Cancer Symposium. Abstract GS5- 06. Presented December 8, 2017.

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