Abemaciclib/Fulvestrant Boosts PFS in HR+/HER2– Breast Cancer Post–CDK4/6i Progression


Key Takeaways

  • Abemaciclib plus fulvestrant significantly improved PFS in hormone receptor-positive, HER2-negative advanced breast cancer patients.
  • The combination therapy showed a median PFS of 5.6 months versus 3.9 months with fulvestrant alone.
Kevin Kalinsky, MD, MS

Kevin Kalinsky, MD, MS

The addition of abemaciclib (Verzenio) to fulvestrant (Faslodex) led to a significant improvement in progression-free survival (PFS) vs fulvestrant alone in patients with hormone receptor–positive, HER2-negative advanced breast cancer who had disease progression on a CDK4/6 inhibitor and endocrine therapy, according to data from the phase 3 postMONARCH study (NCT05169567).

The results, which were presented during the 2024 ASCO Annual Meeting, indicated that the primary end point of investigator-assessed PFS was met at the time of the interim analysis with 70% of the planned events. The doublet (n = 182) led to a median PFS of 5.6 months (95% CI, 5.4-9.2) vs 3.9 months (95% CI, 3.7-5.4) with fulvestrant alone (n = 186; HR, 0.66; 95% CI, 0.48-0.91; P = .01).

Data from the primary analysis, which had 258 events, indicated that the addition of abemaciclib led to a median investigator-assessed PFS of 6.0 months (95% CI, 5.6-8.6) vs 5.3 months (95% CI, 3.7-5.6) with fulvestrant alone, translating to a 27% reduction in the risk of disease progression or death (HR, 0.73; 95% CI, 0.57-0.95; P = .02). The 6-month PFS rates in the respective arms were 50% and 37%.

“postMONARCH is the first randomized, placebo-controlled, phase 3 study to demonstrate benefit of continued CDK4/6 inhibition beyond progression on a CDK4/6 inhibitor,” Kevin Kalinsky, MD, MS, who is the director of the Glenn Family Breast Center at Emory Winship Cancer Institute, in Atlanta, Georgia, said in a presentation of the data.

For patients with hormone receptor–positive, HER2-negative advanced breast cancer, the standard frontline treatment is CDK4/6 inhibition paired with endocrine therapy, Kalinsky said. He added that abemaciclib, which is a CDK4/6 inhibitor that has greater selectivity for CDK4 than CDK6 and hence allows for continuing dosing, is approved for use as a monotherapy in the advanced setting and in combination with endocrine therapy in the advanced setting as well as in high-risk early-stage breast cancer.

“We have previously seen randomized phase 2 trials of continuous CDK4/6 inhibitor after progressing on a CDK4/6 inhibitor and switching the endocrine therapy and these data have demonstrated inconsistent benefit,” Kalinsky underscored. “Recent approvals of targeted therapy after frontline CDK4/6 inhibition had been limited to biomarker-positive advanced disease, including those with PI3K pathway alterations and those with ESR1 mutations.” Despite these advances, the median PFS with these approaches are under 6 months and absolute improvement is generally limited to approximately one to two scan intervals, he added.

The randomized, global, phase 3 postMONARCH study enrolled men and women with hormone receptor–positive, HER2-negative advanced disease. Patients could either have experienced disease progression on a CDK4/6 inhibitor and an aromatase inhibitor as initial therapy in the advanced setting, or disease recurrence on or following adjuvant CDK4/6 inhibition and endocrine therapy. Notably, no other therapy for advanced disease was permitted, “including no prior chemotherapy or SERDs in the advanced setting,” Kalinsky noted.

Study participants (n = 368) were randomly assigned 1:1 to receive abemaciclib plus fulvestrant or placebo plus fulvestrant. The stratification factors were duration of prior CDK4/6 inhibition, visceral metastases, and geographic region.

The primary end point of the study was investigator-assessed PFS, and secondary end points included overall survival (OS), PFS by blinded independent central review (BICR), objective response rate, clinical benefit rate, disease control rate, duration of response, safety, pharmacokinetics, and patient-reported outcomes.

“The study enrolled over 15 months. Scans were performed every 8 weeks for the first 12 months and then every 12 weeks,” Kalinsky said. “This analysis was event-driven, with the primary outcome targeting 251 events, and with an interim analysis planned at [about] 70% of events. Assuming a hazard ratio 0.70, we had around 80% power to detect abemaciclib superiority and the baseline biomarker ctDNA is analyzed by the GuardantINFINITY assay.”

The patient and disease characteristics at baseline were relatively well balanced, he added. The median patient age was 58 years (range, 27-86) in the doublet arm and 61 years (range, 28-85) in the monotherapy arm. Most patients were female (99% vs 100%), not Hispanic/Latino (74% vs 77%), and had measurable disease (72% vs 68%). Slightly more than half had an ECOG performance status of 0 (57% vs 58%). Regarding hormone receptor status in the doublet arm, all patients had estrogen receptor positivity and 79% had progesterone receptor positivity; in the monotherapy arm, these rates were 99% and 81%, respectively. With regard to geographic region in the doublet arm, 12% were from Asia, 15% were from the United States, and 73% were from other (including the European Union; these respective rates were 13%, 15%, and 72% in the monotherapy arm.

Moreover, 62% of patients in the abemaciclib arm had visceral metastasis vs 59% of those in the placebo arm. In the abemaciclib arm, the site of the metastasis was the liver for 37% of patients and the bone only for 18% of patients; these respective rates in the placebo arm were 38% and 23%. All patients in the abemaciclib arm received prior CDK4/6 in the advanced breast cancer setting vs 98% of those on the placebo arm; 2% of patients in the placebo arm received it as adjuvant treatment. Previous CDK4/6 inhibitors included palbociclib (Ibrance; 59% vs 59%), ribociclib (Kisqali; 34% vs 33%), and abemaciclib (8% vs 8%). More than half of patients received prior CDK4/6 inhibitors for a duration of at least 12 months (71% vs 77%).

The investigator-assessed PFS benefit achieved with abemaciclib over placebo was observed across subgroups. “You can see, the interaction P value was not statistically significant for any subgroup, including the prespecified stratification factors of region, visceral metastasis, and prior CDK4/6 inhibitor duration,” Kalinsky said. “While there was a greater magnitude of benefit for patients who did not have visceral metastasis, if you look at liver metastasis, the hazard ratio was about the same. At the bottom of the forest plot, you can see prior CDK4/6 inhibition, and again, 60% [of patients] had prior palbociclib. For those who had prior ribociclib, the hazard ratio is 1.01 although the confidence interval is wide, from 0.67 to 1.51, with less than 100 events. Again, this interaction was not statistically significant, and I would caution with overinterpretation of these data.”

Data from the secondary analysis showed that abemaciclib improved PFS over placebo when assessed by BICR, as well. The median PFS with abemaciclib/fulvestrant was 12.9 months (95% CI, 9.5-not reached) vs 5.6 months (95% CI, 3.9-.7.7) with fulvestrant alone, translating to a 45% reduction in the risk of disease progression or death (HR, 0.55; 95% CI, 0.39-0.77; P = .0004). The 6- month PFS rates in the abemaciclib and placebo arms were 68% and 45%, respectively.

“Of note, there was higher discordance, with more investigator-assessed events compared to those called by central review in the abemaciclib arm compared to the placebo arm,” Kalinsky noted. “The estimates shown here could be impacted by informative censoring, with a likely overestimation of the point estimates.” Data from the BICR-assessed PFS subgroup analysis mirrored what was observed by investigator assessment, he added, but again, the estimates were impacted by informative censoring.

Additional data from the secondary analysis showed that in patients with measurable disease who received the doublet (n = 131), the investigator-assessed ORR was 17% vs 7% with the monotherapy (n = 127; nominal P = .0145). The BICR-assessed ORRs were 23% and 8%, respectively (nominal P = .0008).

Investigators conducted additional subgroup analyses looking at investigator-assessed PFS by prior CDK4/6 inhibitor duration and visceral metastases. In the group who had prior CDK4/6 inhibitor of under 12 months, the median PFS with abemaciclib/fulvestrant (n = 53) was 5.5 months (95% CI, 2.4-9.1) vs 3.0 months (95% CI, 1.9-4.2) with fulvestrant alone (n = 40; HR, 0.80; 95% CI, 0.50-1.29). In those with prior CDK4/6 inhibition duration of 12 months or longer, the median PFS with the doublet (n = 129) was 7.0 months (95% CI, 5.6-9.0) vs 5.4 months (95% CI, 4.0-5.7) with the monotherapy (HR, 0.70; 95% CI, 0.52-0.94). In those without visceral metastases who received the doublet (n = 70) vs the monotherapy (n = 77), the median PFS was 11.1 months (95% CI, 6.3-NR) vs 5.6 (95% CI, 5.3-9.2), respectively (HR, 0.53; 95% CI, 0.34-0.83). In those with visceral metastases, the doublet (n = 112) led to a median PFS of 5.4 months (95% CI, 3.7-5.9) vs 3.7 months (95% CI, 2.0-5.4) with fulvestrant alone (n = 109; HR, 0.87; 95% CI, 0.64-1.17).

Data from an exploratory analysis showed that there was consistent effect across biomarker subgroups. “There was benefit regardless of the presence or absence of ESR1 mutations or PI3K pathway alterations,” Kalinsky said.

The safety data observed on the study were consistent with what has previously been reported with abemaciclib. Only one grade 5 treatment-related adverse effect (AE) of pneumonia was reported in the doublet arm (n = 181). AEs led to dose reductions in 30% of those on the abemaciclib arm vs 3% of those on the placebo arm (n = 185); AEs led to discontinuation in 6% and 0% of patients, respectively.

The most common grade 3 or higher AEs reported in the abemaciclib/fulvestrant arm were neutropenia (25%), anemia (11%), leukopenia (8%), increased aspartate aminotransferase (6%), diarrhea (4%), thrombocytopenia (4%), increased alanine aminotransferase (4%), fatigue (3%), nausea (3%), abdominal pain (2%), vomiting (2%), venous thromboembolism (2%), decreased appetite (1%), arthralgia (1%), and interstitial lung disease (1%).

“Abemaciclib plus fulvestrant offers a targeted therapy option after disease progression on a CDK4/6 inhibitor for patients with hormone receptor–positive/HER2-negative advanced breast cancer, not selected for biomarker status,” Kalinsky concluded.

Disclosures: Dr Kalinsky has employment and stock ownership with EQRx (I) and GRAIL (1). He serves in a consulting or advisory role for 4D Pharma, AstraZeneca, Cullinan Oncology, Daiichi Sankyo/AstraZeneca, eFFECTOR Therapeutics, Genentech/Roche, Immunomedics, Lilly, Menarini Silicon Biosystems, Merck, Mersana, Myovant Sciences, Novartis, Oncosec, Prelude Therapeutics, Puma Biotechnology, RayzeBio, Seagen, and Takeda. Research funding was received from Ascentage Pharma (Inst), Astrazeneca (Inst), Daiichi Sankyo (Inst), Genentech/Roche (Inst), Lilly (Inst), Novartis (Inst), and Seagen (Inst). He also has other relationships with Genentech and Immunomedics.


Kalinsky K, Bianchini G, Hamilton EP, 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. J Clin Oncol. 2024;42(suppl 17):LBA1001. doi:10.1200/JCO.2024.42.17_suppl.LBA1001

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