Abemaciclib improves progression-free survival in HR+/HER2- advanced breast cancer post-CDK4/6 inhibitor progression

For patients with HR+/HER2- advanced breast cancer, a combination of a CDK4/6 inhibitor and endocrine therapy is the standard first-line treatment. Unfortunately, disease progression occurs in almost all patients. Previous studies have shown that treatment with abemaciclib after treatment with a CDK4/6 inhibitor could improve progression-free survival (PFS). This was further investigated in the postMONARCH study. At ASCO 2024, the first results of this phase III study were presented by Kevin Kalinsky, MD (Winship Cancer Institute of Emory University, Atlanta, USA).

A combination of a CDK4/6 inhibitor and endocrine therapy is the standard first-line treatment for patients with HR-positive, HER2-negative advanced breast cancer. Abemaciclib is an oral, potent CDK4/6 inhibitor that is more selective for CDK4 than for CDK6. This drug is the only CDK4/6 inhibitor approved as monotherapy. In addition, abemaciclib in combination with the aromatase inhibitor fulvestrant is approved for the treatment of patients with advanced breast cancer. Clinical phase II studies have suggested that the use of abemaciclib after previous treatment with a CDK4/6 inhibitor could lead to an improved PFS. However, the results are inconsistent and more clarity is required to determine whether abemaciclib in combination with endocrine therapy offers benefit to patients with advanced breast cancer. The postMONARCH study investigated whether treatment with abemaciclib in combination with fulvestrant (endocrine therapy) could prolong PFS in patients with advanced breast cancer in whom disease progression had occurred.

Study design

The phase III trial postMONARCH is a randomised, double-blind, placebo-controlled study conducted in 16 countries. Patients were randomised 1:1 between treatment with abemaciclib plus fulvestrant or placebo plus fulvestrant. Only patients with HR-positive, HER2-negative advanced breast cancer in whom disease progression had occurred after initial treatment with a CDK4/6 inhibitor plus aromatase inhibitor or in whom a recurrence had occurred during or after treatment with a CDK4/6 inhibitor plus endocrine therapy as adjuvant therapy for early breast cancer were eligible to participate. Patients who had previously received other treatments were excluded from participation. The primary outcome measure was PFS, assessed by the investigators. Secondary outcome measures were PFS, assessed by a blinded independent central review board, overall survival (OS), the percentage of patients in whom an objective response was achieved (ORR) and safety.

Results

A total of 368 patients were randomised, of whom 182 patients were treated with abemaciclib plus fulvestrant (N=182; mean age: 58 years) and 186 patients received placebo plus fulvestrant (N= 186; mean age: 61 years). Most patients (99%) participated in the study immediately after treatment with a CDK4/6 inhibitor plus endocrine therapy as initial treatment for advanced breast cancer. Previously used CDK4/6 inhibitors included palbociclib (59%), ribociclib (33%), and abemaciclib (8%). Treatment with abemaciclib plus fulvestrant led to a statistically significantly longer PFS, as assessed by the investigators, than treatment with placebo plus fulvestrant, both at the interim analysis (median 5.6 vs. 3.9 months, HR[95%CI] 0.66[0.48-0.91], p= 0.01) and at the primary analysis (HR[95%CI] 0.73[0.57-0.95]). PFS at 6 months was 50% in the abemaciclib group versus 37% in the placebo group. The positive effect of abemaciclib was observed in key clinical and genomic subgroups, including in patients who had ESR1 or PIK3CA mutations. The PFS, assessed by the central review board, was also longer in the abemaciclib group, compared with the placebo group (median 12.9 vs. 5.6 months, HR[95%CI]: 0.55[0.39-0.77]). Data on OS are still incomplete. The ORR was higher in the abemaciclib group compared with the placebo group (17% vs. 7%). The safety of abemaciclib was in line with the known safety profile. In 30% of patients, the dose of abemaciclib was reduced due to adverse events and in 6% of patients, treatment was discontinued due to adverse events.

Conclusion

This randomised phase III trial has shown that treatment with abemaciclib in combination with fulvestrant leads to a statistically significant improvement in PFS in patients with HR-positive, HER2-negative advanced breast cancer in whom disease progression occurred after previous treatment with a CDK4/6 inhibitor. No new safety signals were observed.

Reference

Kalinsky K, et al. Abemaciclib plus fulvestrant vs fulvestrant alone for HR+, HER2- advanced breast cancer following progression on a prior CDK4/6 inhibitor plus endocrine therapy: primary outcome of the phase 3 postMONARCH trial. Presented at ASCO 2024; abstract LBA1001.