Overall Survival in Two Monarch Trials of Abemaciclib in Advanced Breast Cancer

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Overall survival results from two trials of abemaciclib in advanced breast cancer were reported at the European Society for Medical Oncology (ESMO) Congress 2022. Both MONARCH 3 and monarcHER previously met their primary endpoints of progression-free survival. The current results for overall survival, which was a secondary endpoint in both studies, were not statistically significant, but favorable trends were shown for the addition of abemaciclib to the standard of care.

In the second interim analysis of the phase III MONARCH 3 trial of 493 postmenopausal patients with hormone receptor–positive, HER2-negative advanced breast cancer, abemaciclib plus a nonsteroidal aromatase inhibitor resulted in a median overall survival of 67.1 months, vs 54.5 months with endocrine therapy alone (hazard ratio [HR] = 0.754; P = .0301 [boundary for statistical significance not crossed]).1 In patients with visceral disease, median overall survival was 65.1 months vs 48.8 months (HR = 0.708; P = .0392 [boundary for statistical significance not crossed]).

Statistical significance was not reached [with abemaciclib plus a nonsteroidal aromatase inhibitor], but the data are maturing favorably, and follow-up continues.
— Matthew P. Goetz, MD

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“The observed difference in median overall survival was 12.6 months, and in patients with aggressive disease characteristics [visceral disease], it was 16.3 months. At this interim analysis, although statistical significance was not reached, the data are maturing favorably, and follow-up continues,” said Matthew P. Goetz, MD, Professor of Oncology and Pharmacology at the Mayo Clinic in Rochester, Minnesota.

A previous analysis had shown a highly significant difference in progression-free survival, leading to global regulatory approval of abemaciclib in this setting.2 Median progression-free survival was 28.2 months in the abemaciclib arm and 14.8 months in the control arm (HR = 0.540; P = .000021). At that time, overall survival data were not mature. 

Abemaciclib is a selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. CDK4/6 inhibitors have changed the treatment landscape of advanced breast cancer, and MONARCH 3 was the last of three large, first-line CDK4/6 inhibitor trials to complete enrollment. Compared with two other CDK4/6 inhibitors (ribociclib and palbociclib), abemaciclib’s greater selectivity for CDK4 than CDK6 allows continuous dosing due to less myelosuppression, Dr. Goetz pointed out.

More Findings From MONARCH 3

Consistent overall survival differences were observed across prespecified subgroups, including patients with prior aromatase inhibitor therapy (HR = 0.523). Dr. Goetz emphasized that 31.5% of the control arm subsequently received a CDK4/6 inhibitor after disease progression, compared with 10.1% of the abemaciclib arm.

Updated progression-free survival in the intent-to-treat population showed a median progression-free survival of 29.0 months with abemaciclib vs 14.8 months with endocrine therapy alone (HR = 0.518; P < .0001).

“It’s interesting, as you look across these curves, at 5 years, 9.6% of patients treated with an aromatase inhibitor alone remain progression-free vs 26.7% of patients treated with abemaciclib,” Dr. Goetz noted. The addition of abemaciclib also deferred the initiation of chemotherapy by more than 16 months (HR = 0.636; 95% confidence interval [CI] = 0.505–0.801), he said.

There were no new safety signals in the latest analysis. Final overall survival data are expected in 2023.

Final Overall Survival Results From monarcHER

In the final overall survival analysis of the phase II monarcHER trial, the addition of abemaciclib to trastuzumab, with or without fulvestrant, numerically improved overall survival over standard chemotherapy plus trastuzumab.3 The study enrolled 237 patients with hormone receptor–positive, HER2-positive advanced breast cancer who had received at least two prior anti-HER2 agents.

The 237 patients were randomly assigned 1:1:1 to one of three treatment arms: abemaciclib at 150 mg twice daily, trastuzumab at 8 mg/kg on cycle 1 followed by 6 mg/kg thereafter, and fulvestrant at 500 mg (arm A); abemaciclib plus trastuzumab (arm B); or standard of-care single-agent physician’s choice chemotherapy plus trastuzumab (arm C).

After a median follow-up of 52.9 months, 157 deaths had occurred across the arms, including in 63%, 68%, and 67% of arms A, B, and C, respectively. Median overall survival was 31.1 months in arm A (abemaciclib, trastuzumab, fulvestrant), 29.2 months in arm B (abemaciclib, trastuzumab), and 20.7 months in arm C (chemotherapy, trastuzumab). For arm A vs arm C, the hazard ratio was 0.71 (95% CI = 0.48–1.05; P = .086), and for arm B vs arm C, the hazard ratio was 0.84 (95% CI = 0.57–1.23; P = .365), reported Fabrice André, MD, PhD, Professor of Oncology and Research Director at Gustave Roussy, Villejuif, France.

Fabrice André, MD, PhD

Fabrice André, MD, PhD

In a previous analysis, the primary endpoint was met, with significantly longer progression-free survival in arm A than in arm C (8.3 vs 5.7 months; P = .051).4 No difference was observed between arms B and C. The final progression-free survival and safety outcomes presented at the ESMO Congress were consistent with the earlier data, he said.

An exploratory RNA-sequencing analysis was performed to evaluate the impact of intrinsic breast cancer subtype on outcome. Results of RNA sequencing showed luminal subtypes to be associated with longer progression-free survival and overall survival compared with nonluminal subtypes. Median progression-free survival, for luminal vs nonluminal types, was 8.6 months vs 5.4 months (HR = 0.54; 95% CI = 0.38–0.79), and median overall survival was 31.7 months vs 19.7 months (HR = 0.68; 95% CI = 0.46–1.00). 

DISCLOSURE: Dr. Goetz reported personal financial relationships with Total Health Conferencing, Curio Science, Research to Practice, Clinical Education Alliance, Medscape, and MJH Life Sciences; has served as a consultant and/or advisor for ARC Therapeutics, AstraZeneca, Biotheranostics, Blueprint Medicines, Lilly, RNA Diagnostics, Sanofi Genzyme, and Seagen; and has received institutional grant funding from Lilly, Pfizer, and Sermonix. Dr. André reported no personal financial relationships, although funds received for research and advisory board participation were compensated to his institution.


1. Goetz MP, Toi M, Huober J, et al: MONARCH 3: Interim overall survival results of abemaciclib plus a nonsteroidal aromatase inhibitor in patients with HR+, HER2– advanced breast cancer. ESMO Congress 2022. Abstract LBA15. Presented September 9, 2022.

2. Johnston S, Martin M, Di Leo A, et al: MONARCH 3 final PFS: A randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer 5:5, 2019.

3. André F, Nadal JC, Denys H, et al: Final overall survival for abemaciclib plus trastuzumab ± fulvestrant versus trastuzumab plus chemotherapy in patients with HR+, HER2+ advanced breast cancer (monarcHER): A randomized, open-label, phase II trial. ESMO Congress 2022. Abstract LBA18. Presented September 10, 2022.

4. Tolaney SM, Wardley AM, Zambelli S, et al: Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): A randomised, open-label, phase 2 trial. Lancet Oncol 21:763-775, 2020.

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