A pooled analysis evaluating the efficacy and safety of the combination of a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and an aromatase inhibitor as first-line treatment for women with hormone receptor-positive, HER2-negative metastatic breast cancer found that older and younger postmenopausal women had similar benefits from this treatment, but older women experienced more toxicity. The findings, which included data from 3 randomized clinical trials, were published in the Journal of Clinical Oncology.

The combination of endocrine therapy with a CDK4/6 inhibitor is currently considered a first-line option for postmenopausal women with hormone receptor-positive, HER2-negative breast cancer based on the results of phase 3 clinical trials evaluating the clinical effect of endocrine therapy (ie, an aromatase inhibitor or fulvestrant) with and without concomitant administration of a CDK4/6 inhibitor (eg, palbociclib, ribociclib, abemaciclib). Despite the high percentage of older women with breast cancer, this population, particularly those age 75 years and older, were underrepresented in these and other trials involving women with breast cancer. Hence, clinical data on which to base the counseling of older patients who are considering endocrine therapy in combination with a CDK4/6 inhibitor are limited.

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This research included 1105 patients enrolled in the PALOMA-2 (ClinicalTrials.gov identifier; NCT01740427; letrozole with or without palbociclib), MONALEESA- 2 (ClinicalTrials.gov identifier: NCT01958021; letrozole with or without ribociclib), or MONARCH-3 (ClinicalTrials.gov identifier: NCT02246621; anastrozole or letrozole with or without abemaciclib) phase 3 clinical trials who had received treatment with a CDK4/6 inhibitor in combination with an aromatase inhibitor.

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Within this group of patients, 456 (25%) and 198 (10.8%) were at least 70 or 75 years of age, respectively. The primary end point of all 3 studies was progression-free survival (PFS); all patients were postmenopausal, had hormone receptor-positive, HER2-negative breast cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and had not received previous therapy for metastatic disease.

For the overall patient cohort, the estimated median PFS was 14.8 months for those receiving an aromatase inhibitor alone and 27.7 months for those treated with an aromatase inhibitor in combination with a CDK4/6 inhibitor (hazard ratio [HR], 0.55; 95% CI, 0.48-0.63). Corresponding results were 19.2 months and 33.1 months (HR, 0.52; 95% CI, 0.38-0.70) for patients aged 70 years and older, and 13.7 months and 24.9 months (HR, 0.49; 95% CI, 0.31-0.76) for those aged 75 years and older.

A comparison of the safety of the combination of a CDK4/6 inhibitor plus and aromatase inhibitor in 2 patient subgroups (younger than age 75 years or 75 years or older) showed a higher rate of grade 3/4 toxicities in older patients (88.8% vs 73.4%). In addition, patients aged 75 years or older experienced higher rates of dose reduction/interruption (81.6% vs 71.1%) and treatment discontinuation (32.0% vs 12.1%).

Specifically, patients aged 75 years or older were more likely than their younger counterparts to experience diarrhea (53.6% vs 45.5%) and fatigue (54.4% vs 44.3%) when undergoing treatment with a CDK4/6 inhibitor in combination with an aromatase inhibitor.

In addition, for patients 70 years and older receiving combination therapy, dose reductions/interruptions occurred more commonly in cycles 1 to 3, and neutropenia, diarrhea, and increased creatinine were the most common adverse events associated with dose reductions/interruptions.

The study authors concluded that “patients across age groups derive similar benefit in PFS from CDK4/6 inhibitors,” and that supportive care measures may increase the tolerability of this treatment regimen in older patients with breast cancer.


Howie LJSingh HBloomquist E, et al. 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 [published online September 27, 2019]. J Clin Oncol. doi:10.1200/JCO.18.02217