New Paper Alert: Adjuvant CDK4/6 Inhibitors: Promising or Problematic? A Critical Review of the Evidence.

CDK4/6 inhibitors, widely celebrated for their role in managing metastatic ER-positive breast cancer, have garnered growing interest as potential components of adjuvant therapy in early-stage disease. In their article published in the Journal of Clinical Oncology, Tannock et al. critically assess this evolving practice, arguing that current evidence does not support routine adjuvant use of these agents. Drawing on data from major trials—PENELOPE-B, PALLAS, monarchE, and NATALEE—the authors highlight concerns related to trial design, toxicity, lack of overall survival benefit, and the potential acceleration of endocrine resistance. Their analysis calls for caution and underscores the importance of ensuring long-term benefit before integrating CDK4/6 inhibitors into curative-intent treatment strategies.

Title: Why We Do Not Recommend That Women With Breast Cancer Receive Adjuvant Treatment With a CDK4/6 Inhibitor

Authors: Ian F. Tannock, MD, PhD, Qamar J. Khan, MD, Tito Fojo, MD, PhD

Published in JCO Oncology, April 2025

Background

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors—palbociclib, abemaciclib, and ribociclib—have demonstrated efficacy in metastatic estrogen receptor–positive (ER+) breast cancer, particularly when combined with endocrine therapy. This success prompted investigations into their potential benefits as adjuvant treatments in early-stage ER+ breast cancer. However, the article “Why We Do Not Recommend That Women With Breast Cancer Receive Adjuvant Treatment With a CDK4/6 Inhibitor” by Tannock et al. raises concerns about their use in this setting, highlighting issues related to toxicity, trial design, and potential for endocrine resistance.​

Methods

The authors critically analyze data from four randomized controlled trials (RCTs): PENELOPE-B, PALLAS, monarchE, and NATALEE. These studies compared standard adjuvant endocrine therapy alone versus in combination with a CDK4/6 inhibitor in patients with early-stage ER+ breast cancer. The primary endpoint across these trials was invasive disease-free survival (iDFS), with overall survival (OS) as a secondary endpoint.​

Study Design

• PENELOPE-B and PALLAS: Assessed palbociclib plus endocrine therapy; both trials did not show improvement in iDFS.
• monarchE: Evaluated 2 years of abemaciclib plus endocrine therapy in high-risk patients; reported iDFS improvement.
• NATALEE: Investigated 3 years of ribociclib plus endocrine therapy in stage II/III patients; also reported iDFS improvement.​

Notably, monarchE and NATALEE each enrolled over 5,000 patients and led to regulatory approvals for adjuvant use of abemaciclib and ribociclib.​

Results

Toxicity of Treatment

monarchE trial:

Extended use of CDK4/6 inhibitors in the adjuvant setting resulted in significant toxicity
monarchE:

• ​60% experienced treatment interruptions due to adverse events (AEs).
• ​40% required dose reductions.
• Two treatment-related deaths reported.​

NATALEE trial:

• 31% discontinued ribociclib due to AEs or other reasons.
• 19.7% discontinued their nonsteroidal aromatase inhibitor (NSAI).
• 25 deaths occurred in the ribociclib arm without disease progression, compared to 16 in the control arm.​

Financial toxicity is also a concern, with full courses of adjuvant abemaciclib and ribociclib costing approximately $300,000 and $500,000 USD, respectively.​

Failure to Provide Optimal Postprogression Treatment to Control Patients

The trials did not ensure that patients in the control arms received CDK4/6 inhibitors upon disease recurrence, potentially biasing OS results. For instance, in monarchE, the 5-year OS difference between arms was less than 1%, with no significant difference observed. In NATALEE, OS data remain immature, with a median follow-up of 44.3 months and a difference of 16 deaths among 5,101 patients between arms.

High Prevalence of Censoring Renders monarchE and NATALEE Trials Uninterpretable

Informative censoring—where dropout is related to treatment or prognosis—was prevalent

monarchE:

• Approximately 9.2% censored for iDFS and 9.8% for OS in the abemaciclib group.
• Approximately 8.0% censored for iDFS and 9.2% for OS in the control group.​

NATALEE:

• Approximately 19.4% censored for iDFS and 16.1% for OS in the ribociclib group.
• Approximately 23.5% censored for iDFS and 21% for OS in the control group.​

Such high censoring rates, especially if informative, can bias results and undermine the validity of trial conclusions.​

CDK4/6 Inhibitors May Accelerate Development of Endocrine Resistance

Emerging biological evidence suggests that the use of CDK4/6 inhibitors in the adjuvant setting may paradoxically contribute to earlier onset of endocrine resistance in ER+ breast cancer. A key insight into this concern comes from the FELINE trial, a neoadjuvant window-of-opportunity study evaluating the combination of ribociclib with letrozole in early-stage ER+/HER2− breast cancer.

The trial found that while ribociclib initially suppressed cellular proliferation—as indicated by reduced Ki-67 levels—this suppression was not sustained over time. With continued treatment, Ki-67 expression levels began to rise again in tumors exposed to ribociclib, implying that tumor cells were adapting to the antiproliferative pressure. This rebound effect suggested the emergence of proliferative escape mechanisms, even in the context of ongoing CDK4/6 inhibition.

To further explore the biological underpinnings of this resistance, the investigators employed single-cell RNA sequencing. The high-resolution transcriptomic analysis revealed a shift in tumor cell signaling pathways, with subpopulations of cancer cells transitioning away from reliance on estrogen receptor (ER) signaling and instead activating alternative proliferative pathways, such as those mediated by growth factor receptors and intracellular kinase cascades (e.g., PI3K/AKT and MAPK pathways).

This phenotypic plasticity—wherein cancer cells alter their transcriptional programs to escape drug pressure—raises major concerns in the adjuvant setting, where long-term disease control depends on sustained endocrine sensitivity. The potential for CDK4/6 inhibitors like ribociclib to promote a switch from estrogen-dependent to estrogen-independent growth could not only undermine the efficacy of endocrine therapy but also lead to earlier relapse with more aggressive, treatment-refractory disease.

Based on this evidence, the long-term biological consequences of using CDK4/6 inhibitors in curative-intent settings remain uncertain. The FELINE trial highlights the importance of incorporating molecular endpoints into adjuvant trials and calls into question whether short-term improvements in invasive disease-free survival (iDFS) may come at the cost of long-term therapeutic resistance.

Key Findings

While CDK4/6 inhibitors have transformed the management of metastatic ER+ breast cancer, their role in the adjuvant setting remains questionable. The trials reviewed exhibit significant limitations, including toxicity, financial burden, inadequate postprogression treatment strategies, and high censoring rates. Until more definitive evidence emerges, the routine use of CDK4/6 inhibitors as adjuvant therapy in early-stage ER+ breast cancer should be approached with caution
CDK4/6 inhibitors in the adjuvant setting offer marginal iDFS benefits with significant toxicity and financial burden.

• Trial designs lacked provisions for optimal postprogression treatment in control groups, potentially skewing OS outcomes.
• High and potentially informative censoring rates compromise the interpretability of trial results.
• Evidence suggests possible acceleration of endocrine resistance with adjuvant CDK4/6 inhibitor use.

Key Takeaway Messages

• The modest benefits of adjuvant CDK4/6 inhibitors do not outweigh the associated risks and costs.
• Robust trial designs, including provisions for postprogression treatments and transparent reporting of censoring, are essential.
• Further research is needed to understand the long-term implications of CDK4/6 inhibitors in early breast cancer.

You can read the full article here.

Also you can cheak out our summary of PALMARES-2 study which provides a real word data comparing CDK4/6 inhibitors.