CDK4/6 Inhibitors for Advanced Hormone Receptor–Positive Breast Cancer, 2019 and Beyond

A lthough endocrine therapy has been shown to be beneficial for metastatic hormone receptor-positive (HR1) breast cancer, most patients will ultimately die of the disease.Improved understanding of mechanisms of resistance has resulted in the development of combinations of endocrine therapy with biologic agents, leading to improved outcomes.In particular, CDK4/6 inhibitors have recently been positioned as standard treatment of metastatic HR1 breast cancer.To date, 3 CDK4/ 6 inhibitors are approved for treatment of this patient population: palbociclib, ribociclib, and abemaciclib.CDK4/6 inhibitor therapy in combination with aromatase inhibitors (AIs) and the selective estrogen receptor degrader fulvestrant have demonstrated efficacy for postmenopausal women. 1 Further data support use of ribociclib in premenopausal women and abemaciclib monotherapy for heavily pretreated patients.1 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) now list regimens including a CDK4/6 inhibitor in combination with an AI or fulvestrant as preferred treatment options in patients with metastatic HR1, HER2-negative breast cancer. 1 Palbociclib was the first CDK4/6 inhibitor to be approved.The phase III PALOMA-2 study, which randomized 666 postmenopausal women with advanced HR1, HER2negative breast cancer to first-line treatment with letrozole in combination with palbociclib versus placebo, showed that median progression-free survival (mPFS) was significantly improved in patients treated with palbociclib (24.8 vs 14.5 months; hazard ratio [HR], 0.58; 95% CI, 0.46-0.72;P,.001). 2 Subsequently, the phase III PALOMA-3 study evaluated fulvestrant with palbociclib versus placebo in patients who experienced disease progression while on endocrine therapy.Again, significant improvement in mPFS was observed in patients treated with palbociclib (9.5 vs 4.6 months; HR, 0.46; 95% CI, 0.36-0.59;P,.001).3 Overall survival (OS) is a challenging end point to evaluate in treatments administered early in the treatment course for metastatic HR1 breast cancer, partly due to increasingly long survival rates, typically measured in years.Additionally, because numerous treatment options are available, individual patients will often receive multiple and varied treatments subsequent to early lines of therapy.Although OS data for PALOMA-2 have yet to be reported, survival data were recently published for PALOMA-3 at 44.8 months' median follow-up.OS analysis of the entire study population revealed an absolute benefit of 6.9 months favoring the palbociclib group, but not reaching statistical significance.However, prespecified subgroup analysis demonstrated a statistically significant absolute benefit of 10 months (39.7 vs 29.7 months; HR, 0.46; 95% CI, 0.36-0.59) in patients who had previously been sensitive to endocrine therapy.4 In the article by Xi et al 5 elsewhere in this issue, the authors report on a retrospective analysis of palbociclib combined with endocrine therapy for metastatic HR1 breast cancer at a single academic institution.Although clinical trials are evaluating the management of patients after disease progression on CDK4/6 See page 141 for related article.