Adjuvant CDK4/6 Inhibition Is Not Yet a Clear Winning Strategy in HR+/HER2- Breast Cancer

Conflicting results from the phase 3 monarchE, PENELOPE-B, and PALLAS trials have thrown the role of adjuvant CDK4/6 inhibition into question in patients with high-risk, early-stage hormone receptor–positive, HER2-negative breast cancer.

Conflicting results from the phase 3 monarchE (NCT03155997), PENELOPE-B (NCT01864746), and PALLAS (NCT02513394) trials have thrown the role of adjuvant CDK4/6 inhibition into question in patients with high-risk, early-stage hormone receptor–positive, HER2-negative breast cancer, explained Gini Fleming, MD, FASCO, who added that the differences in outcomes are unlikely due to adherence or agent efficacy, but rather differences in the patient populations, length of follow-up, and duration of therapy.

In monarchE, patients with node-positive, high-risk, early hormone receptor–positive, HER2-negative breast cancer were grouped into 1 of 2 cohorts based on clinicopathological risk and Ki-67, respectively, and randomized to 150 mg of abemaciclib (Verzenio) twice daily for up to 2 years plus standard endocrine therapy or endocrine therapy alone.

Patients with at least 4 positive axillary lymph nodes or 1 to 3 positive axillary lymph nodes and histologic grade 3 disease or tumor size of at least 5 cm were included in cohort 1. Patients with 1 to 3 positive axillary lymph nodes, centrally tested Ki-67 of at least 20%, and no grade 3 disease or tumor size of at least 5 cm were included in cohort 2.

The primary results indicated that abemaciclib/endocrine therapy reduced the risk of invasive disease by 25.3% vs endocrine therapy alone (HR, 0.747; 95% CI, 0.598-0.932; 2-sided P = .0096). The 2-year invasive disease-free survival (IDFS) rates were 92.2% in the abemaciclib/endocrine therapy arm vs 88.7% in the endocrine-alone arm.1

Additional results demonstrated that the addition of abemaciclib to endocrine therapy had a significant impact on distant relapse-free survival (DRFS) across all prespecified subgroups, reducing the risk of distant recurrence by 28.3% (HR, 0.717; 95% CI, 0.559-0.920; P = .0085). The 2-year DRFS rates were 93.6% with abemaciclib/endocrine therapy vs 90.3% with endocrine therapy alone.

Updated findings demonstrated that the risk of developing an IDFS event was reduced by 28.7% with abemaciclib/endocrine therapy (HR, 0.713; 95% CI, 0.583-0.871; P = .0009).2 The 2-year IDFS rates were 92.3% in the abemaciclib/endocrine therapy arm vs 89.3% in the endocrine-alone arm. Moreover, the risk of distant recurrence was reduced by 31.3% with abemaciclib/endocrine therapy (HR, 0.687; 95% CI, 0.551-0.858; P = .0009). The 2-year DRFS rates were 93.8% with abemaciclib/endocrine therapy vs 90.8% with endocrine therapy alone.

“Nothing new or unexpected was seen in terms of toxicity. However, a number of dose reductions and holds were needed primarily for diarrhea and neutropenia,” said Fleming, a professor of medicine and medical director of Gynecologic Oncology at the University of Chicago Medicine, during an OncLive® Institutional Perspectives in Cancer webinar on breast cancer.

In PENELOPE-B, patients were randomized to 125 mg of palbociclib once daily on days 1 through 21 of every 28-day cycle for 1 year (13 cycles) or placebo. Eligible patients included those with hormone receptor-positive, HER2-negative disease who did not achieve a pathologic complete response to neoadjuvant chemotherapy and a CPS-EG score of at least 3 or at least 2 with ypN+ prior to undergoing surgery with or without radiotherapy. All patients received endocrine therapy according to local standards.

“The selection factor besides not having a complete response depended on a marker called CPS-EG, which combined grade, stage, and the estrogen receptor status,” said Fleming.

Results showed that at a median follow-up of 42.8 months, the number of IDFS events in the palbociclib/endocrine therapy arm was 152 vs 156 in the placebo/endocrine therapy arm (stratified HR, 0.93; 95% CI, 0.74-1.17; = .525).3 At 2 years, the estimated IDFS rates were 88.3% and 84.0%, respectively. Moreover, the estimated 3-year IDFS rates were 81.2% with palbociclib vs 77.7% with placebo, while the 4-year IDFS rates were 73.0% vs 72.4%, respectively.

“At the time of the initial analysis, which was about the same time as the monarchE is currently reporting, there was an absolute difference of 4%, which was not too different from what the monarchE study is currently seeing. However, as time went on, this difference disappeared, so that now, with a mean follow-up of 43 months, there is absolutely no difference in the number of IDFS events,” said Fleming.

“PENELOPE-B, which selected for a lack of response to neoadjuvant therapy might have enriched for luminal A tumors, which clearly don’t respond to neoadjuvant therapy, regardless of size, and also, in metastatic disease, appear to benefit much less from the addition of a CDK4/6 inhibitor than do the luminal B tumors or other subtypes of [hormone receptor]-positive cancer,” added Fleming.

In PALLAS, patients were randomized to 125 mg of palbociclib once daily in a 3-weeks-on, 1-week-off schedule plus endocrine therapy for 1 year or endocrine therapy alone.

Eligible patients included those with stage II or III hormone receptor-positive, HER2-negative breast cancer who had completed prior surgery with or without chemotherapy and radiation within 12 months of diagnosis and 6 months of starting adjuvant endocrine therapy. Patients must have also submitted a formalin-fixed paraffin-embedded tissue specimen.

Of note, patients in PENELOPE-B and PALLAS had positive or negative nodes, whereas monarchE only enrolled a lymph node–positive population, explained Fleming.

“PALLAS unlike [PENELOPE-B] was an open-label trial and included some lower-risk patients, such as those with stage IIA vs IIB or IIC disease,” said Fleming.

At a median follow-up of 23.7 months, the 3-year IDFS rate was 88.2% with palbociclib/endocrine therapy vs 88.5% with endocrine therapy alone (HR, 0.93; 95% CI, 0.76-1.15; P = .51).4 The 3-year DRFS rate was 89.3% and 90.7%, respectively (HR, 1.00; 95% CI, 0.79-1.27; P = .9997).

Regarding treatment discontinuation rates across all 3 trials, approximately 28% of patients discontinued abemaciclib in monarchE, and 20% of patients discontinued palbociclib in PENELOPE-B, whereas approximately 42% of patients discontinued palbociclib early in PALLAS.

“Analyses presented at the 2020 San Antonio Breast Cancer Symposium pretty much eliminated [the differences in discontinuation] as a reason for the difference [in outcomes],” said Fleming.

“We can hypothesize that it’s the agent that’s [response for] the difference [in outcomes], but we certainly don’t have evidence of a large difference based on results in metastatic disease,” said Fleming. “At this time, reasons for the difference in outcomes remain unclear. We are awaiting longer follow-up from these trials and results from the NATALEE trial with ribociclib [Kisqali],” Fleming concluded.


  1. Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2-, node-positive, high risk, early breast cancer (monarchE). J Clin Oncol. 2020;38(34):3987-3998. doi: 10.1200/JCO.20.02514.
  2. O’Shaughnessy J, Johnston SRD, Harbeck N, et al. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer. Cancer Res. 2021;81(4). doi:10.1158/1538-7445.SABCS20-GS1-01
  3. Loibl S, Marmé F, Martin M, et al. Phase III study of palbociclib continued with endocrine therapy in patients with hormone-receptor-positive, HER2-negative primary breast cancer and high relapse risk after neoadjuvant chemotherapy: first results from the PENELOPE-B. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Abstract GS1-02.
  4. Mayer EL, Gnant MI, DeMichele A, et al. PALLAS: a randomized phase III trial of adjuvant palbociclib with endocrine therapy versus endocrine therapy alone for HR+/HER2- early breast cancer. Ann Oncol. 2020;31(suppl 4):S1145. doi:10.1016/j.annonc.2020.08.2240