CDK4/6 inhibitors have been proven to improve progression-free survival in women with advanced-stage hormone receptor-positive, HER2-negative breast cancer, resulting in approvals of three different agents (abemaciclib, ribociclib and palbociclib), in combination with endocrine therapies, in both first-line and second-line indications. Now, two of these drugs have been shown in phase III trials to prolong overall survival (OS) in this population.

In MONARCH 2, 669 women with disease progression on prior endocrine therapy were enrolled, regardless of menopausal status, and randomly assigned (2:1) to receive fulvestrant plus either abemaciclib or placebo. Data reported at the ESMO Congress 2019 and in JAMA Oncology demonstrate a median OS of 46.7 months in the abemaciclib arm versus 37.3 months in the placebo arm (HR 0.76, 95% CI 0.61–0.95; P = 0.01). Subgroup analyses revealed that the degree of benefit from abemaciclib was generally consistent, although perhaps greater in women with high-risk disease characteristics, specifically visceral metastases (HR 0.68, 95% CI 0.51–0.89) and/or early resistance to endocrine therapy (HR 0.69; 95% CI 0.45–1.04), and lower in those with bone-only disease (HR 0.91, 95% CI 0.56–1.46).

In MONALEESA-3, 726 women were randomly allocated (2:1) to receive fulvestrant plus ribociclib or placebo; however, unlike in MONARCH 2, only postmenopausal women were enrolled, including a subset without progression on initial endocrine therapy. As also reported at the ESMO Congress 2019, OS was superior with ribociclib (median not reached versus 40 months with placebo; HR 0.72, 95% CI 0.57–0.92; P = 0.0046). Notably, ribociclib provided a similar level of benefit when used in the first line (HR 0.70, 95% CI 0.48–1.02) or second line (HR 0.73, 95% CI 0.53–1.00), as well as across all patient subgroups. These results expand on the OS benefits demonstrated in premenopausal or perimenopausal women in MONALEESA-7.

In both MONARCH 2 and MONALEESA-3, CDK4/6 inhibition also increased time to second disease progression. Importantly, no new safety signals were observed in either trial.

These findings validate the currently approved indications for CDK4/6 inhibitors.

These findings validate the currently approved indications for CDK4/6 inhibitors. Studies are now warranted to refine selection of the optimal CDK4/6 inhibitor for each patient and to overcome resistance to these agents. Predictive biomarkers to identify patients who do not benefit from CDK4/6 inhibition are also required, as emphasized by the late separation of the OS curves, and might be particularly important to the ongoing efforts to move these drugs into the adjuvant setting.