Adjuvant CDK4/6 inhibitors and novel therapies in early breast cancer: lessons from monarchE overall survival data

Introduction

Adjuvant endocrine therapy (ET) remains central to managing HR⁺/HER2⁻ early breast cancer, but high-risk patients face ongoing recurrence risk. Recent trials—including monarchE, NATALEE, OlympiA, lidERA, and POTENT—have explored adjuvant therapies such as CDK4/6 inhibitors, PARP inhibitors, selective estrogen receptor degraders (SERDs), and chemotherapy. The recent update confirmed an overall survival (OS) benefit with abemaciclib in monarchE, prompting a reevaluation of treatment strategies and policy implications.

monarchE establishes OS benefit

monarchE trial design

The phase III monarchE trial evaluated 2 years of the CDK4/6 inhibitor abemaciclib plus standard endocrine therapy (ET) versus ET alone in HR⁺/HER2⁻ node-positive early breast cancer. Eligible patients had high-risk disease: either ≥4 positive axillary nodes, or 1–3 nodes with tumor grade 3 or tumor ≥5 cm (cohort 1); an additional cohort 2 enrolled patients with 1–3 nodes and Ki-67 ≥20% who did not meet cohort 1 criteria. The combination had previously shown a significant invasive disease-free survival (iDFS) advantage, leading to regulatory approval in this high-risk population (initially with a Ki-67 ≥20% requirement in the U.S., now removed) (1).

OS and iDFS outcomes

With 76-month median follow-up, monarchE has now demonstrated a statistically significant OS benefit (2). Abemaciclib + ET reduced the risk of death by around 16% versus ET alone [hazard ratio (HR) =0.84, 95% CI: 0.72–0.98; P=0.027]. The 7-year OS rates were 86.8% with abemaciclib versus 85.0% with ET (an absolute difference of 1.8%) (2). This 1.8% absolute OS difference at 7 years corresponds to an approximate number needed to treat (NNT) of ~56 (1/0.018), noting that NNT is time-dependent and population-specific. The OS signal should therefore be interpreted alongside the 2-year treatment burden (toxicity management, adherence/discontinuation) and the possibility of financial toxicity across health systems. While the absolute OS gain appears modest, it is clinically meaningful given the typically favorable baseline prognosis and the difficulty of showing OS improvement in this setting. Notably, fewer patients on abemaciclib had died or were living with metastatic disease at analysis (6.4% vs. 9.4% living with recurrence). Abemaciclib’s previously reported iDFS benefit was sustained (1), with a 26% reduced risk of invasive recurrence (iDFS HR 0.73) and a 7-year iDFS of 77.4% versus 70.9% (absolute +6.5%) (2). Distant relapse-free survival (DRFS) likewise remained improved (HR 0.75). These results confirm that adding abemaciclib to ET not only delays recurrence but also improves long-term survival in high-risk HR⁺ early breast cancer.

Clinical significance

The OS benefit from monarchE marks a milestone; it is the first time a CDK4/6 inhibitor in early breast cancer has extended survival. The absolute OS difference of 2% at 7 years must be interpreted in context: with 7-year OS 85% on ET alone, preventing even a small number of late metastatic deaths is impactful for patients. In the intention-to-treat population, among patients who developed distant metastatic disease or died, the proportion of patients alive with metastatic disease was 6.4% in the abemaciclib plus ET group versus 9.4% in the ET-alone group. This difference suggests a potential reduction in mortality of nearly 3%, depending on future outcomes.

Moreover, the benefit was consistent across subgroups, including both cohort 1 and 2, suggesting broad utility. These data solidify adjuvant abemaciclib + ET as a standard of care for those with node-positive, high-risk disease. In the United States, the FDA has expanded the indication to all high-risk patients as defined in monarchE, dropping the prior Ki-67 ≥20% requirement. This change reflects confidence that the drug’s benefit is not confined to tumors with high proliferation index, a point supported by the subgroup analyses and the OS gain observed. From a health policy perspective, demonstrating OS improvement may also influence reimbursement and guideline endorsement in various regions, since some payers and clinicians awaited this definitive endpoint before embracing routine use due to cost and toxicity considerations.

Toxicity and tolerability

Adjuvant abemaciclib does carry notable side effects. The most common adverse events (AEs) are diarrhea, neutropenia, fatigue, leukopenia, infections, nausea, anemia, and headache. Diarrhea is especially prominent (any-grade in 80% of patients in trials, though grade ≥3 in 8%) and requires proactive anti-diarrheal management. Cytopenias are frequent (e.g., grade ≥3 neutropenia in 19%), but febrile neutropenia is rare (1,2). In monarchE, therapy discontinuations due to AEs were manageable, and long-term safety data showed no emergent late toxicities. Overall, the risk-benefit profile is favorable in the high-risk population, given the significant reduction in recurrence and now mortality.

Expanding the adjuvant armamentarium

Multiple phase III trials in recent years have tested therapy intensification in early breast cancer, targeting patients at significant risk of recurrence. Each trial addresses a different strategy: CDK4/6 inhibition (monarchE, NATALEE), PARP inhibition (OlympiA), oral SERD (lidERA), and extended chemotherapy (POTENT). The results of each clinical trial are summarized in Table 1.

NATALEE trial (ribociclib + ET)

The NATALEE trial enrolled a broad population with stage IIA (including some N0 with high-risk features: Ki-67 >20%, Oncotype DX >26, etc.) to III disease (N=5,101) (3). Patients received ribociclib 400 mg QD 3 weeks on/1 week off × 3 years plus AI (± goserelin if premenopausal) versus AI ± goserelin alone (4). At 2.8 years median follow-up, iDFS showed HR 0.75 (0.63–0.89), with 3-year iDFS 90.7% versus 87.6% (4). OS was not mature with no significant OS difference yet (4). Notable AEs included neutropenia (any 62%, G≥3 in 44%), elevated aspartate aminotransferase (AST)/alanine aminotransferase (ALT) (26% any), QT prolongation (5% G1–2), and rare interstitial lung disease/pneumonitis (1.5%) (4). At the primary efficacy analysis, adjuvant ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) improved iDFS versus NSAI alone. In the prespecified 5-year analysis, it is important to distinguish the 5-year landmark efficacy estimates from the median iDFS follow-up, which was 55.4 months at this data cut. Ribociclib + NSAI maintained a durable iDFS benefit (hazard ratio 0.716), with 60-month iDFS 85.5% vs. 81.0% (absolute Δ4.5%), and an emerging but still statistically immature OS trend (hazard ratio 0.800; 95% CI crossing 1.0). These longer-term data support sustained benefit beyond the 3-year ribociclib treatment window while underscoring that OS remains an evolving endpoint in this setting (5).

OlympiA trial (olaparib)

OlympiA enrolled 1,836 patients with germline BRCA1/2-mutated, HER2⁻, high-risk (primarily stage II–III) disease after surgery and (neo)adjuvant chemotherapy (6). Patients received olaparib 300 mg BID × 1 year versus placebo, after standard chemotherapy ± radiotherapy and ET (if ER⁺) (6). At 6.1 years median follow-up, iDFS showed HR 0.65; 6-year iDFS 79.6% versus 70.3% (6). OS showed HR 0.72; 6-year OS 87.5% versus 83.2% (7). Common AEs included anemia and fatigue, neutropenia, and nausea. Importantly, there was no excess myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) (4 vs. 6 cases on placebo).

lidERA trial (giredestrant)

The lidERA trial evaluated giredestrant, a novel oral SERD, in ER⁺ medium or high-risk stage I-III disease (e.g., node+ or other risk; any ESR1 mutational status; N=4,100) (8). Patients received giredestrant 30 mg QD ≥5 years versus standard ET (AI or tamoxifen ×5 years; ovarian function suppression if needed). At 2–3 years interim analysis, iDFS showed HR 0.70 (98% CI: 0.55–0.88); 30% reduction in recurrence risk, the first adjuvant oral SERD to beat standard ET (8). OS data were immature with a trend favoring giredestrant. Adverse events were similar to AI therapy with arthralgia and hot flashes. Lower treatment discontinuation versus AI (1.8% vs. 4.4%) was noted due to better tolerability. Mild bradycardia was observed in 11% (grade 1–2). These landmark results, presented at SABCS 2025, mark the first improvement in adjuvant ET in over 20 years and position giredestrant as a potentially new standard of care.

POTENT trial (S-1 + ET)

POTENT was a Japan-only trial in stage I-III, ER⁺/HER2⁻ disease with intermediate or high relapse risk (N=1,939) (9). Patients received S-1 (oral fluoropyrimidine prodrug) 80–120 mg QD days 1–28/42 for 1 year + ET versus ET alone. At 4.3 years interim analysis (6.5-year final follow-up), iDFS showed HR 0.63 at 5 years (estimated 5-year iDFS 86.9% vs. 81.6%) (9). The benefit persisted but narrowed at 6 years (iDFS HR 0.80, P=0.06) with significant distant disease-free survival improvement (HR 0.70) (10). OS showed no significant difference (6-year OS 94.4% vs. 93.1%, HR 0.89) (10). Adverse events included bone marrow suppression (neutropenia), gastrointestinal toxicities (nausea, diarrhea), hyperpigmentation changes, and fatigue. The regimen was generally well tolerated, with Asian-specific tolerability noted.

Trial insights: patient selection and biomarkers

These trials underscore that patient selection is critical when intensifying therapy. All of the positive studies above focused on patients with high relapse risk—defined by anatomic stage, nodal status, tumor grade/size, or biomarkers like Ki-67 or BRCA status. Notably, the Ki-67 proliferation index played a role in trial designs. monarchE initially included a Ki-67 ≥20% criterion for cohort 2 and this subset did not show a clear iDFS benefit at first analysis (more deaths were observed on abemaciclib in cohort 2, albeit in small numbers). Consequently, approval was initially restricted to Ki-67-high tumors in US. However, with larger data maturity, Ki-67 appears less discriminatory for abemaciclib benefit, leading the FDA to remove the Ki-67 requirement. Ki-67 was also used in NATALEE to identify “high-risk” node-negative patients (e.g., grade 2 tumors with Ki-67 >20% qualified). These approaches reflect an effort to spare lower-risk patients from unnecessary toxicity. Moving forward, better biomarkers [genomic risk scores, gene expression profiles, or circulating tumor DNA (ctDNA)] could refine selection beyond crude clinico-pathologic features and Ki-67. Beyond static clinicopathologic features, ctDNA assays may identify molecular residual disease (MRD) or molecular relapse before radiographic recurrence. In this context, European Organisation for Research and Treatment of Cancer, EORTC-2129-BCG (TREAT ctDNA, NCT05512364) is evaluating a ctDNA-informed strategy by randomizing patients with ctDNA relapse and no detected metastasis to switch ET to elacestrant versus continue standard adjuvant ET (Table 2). While ctDNA-guided escalation may enable risk-adapted intensification and potentially reduce overtreatment, its clinical utility remains investigational, with key uncertainties including assay standardization, false positives/negatives, lead-time bias, and whether early intervention improves hard endpoints.

Another insight is the heterogeneity of CDK4/6 inhibitor results. The success of abemaciclib (monarchE) and ribociclib (NATALEE) contrasts with the failure of palbociclib in the PALLAS and PENELOPE-B trials (11-13). PALLAS (palbociclib 2 years + ET in stage II-III) ultimately showed no iDFS or OS improvement versus ET, 4-year iDFS 84% in both arms (HR =1.0) (11). Longer follow-up confirmed the absence of a meaningful survival advantage (12). Similarly, the PENELOPE-B trial in patients with residual high-risk disease after neoadjuvant chemotherapy also failed to demonstrate improved outcomes with palbociclib (13).

The reasons remain debated. Differences in dosing schedule (continuous daily dosing for abemaciclib versus 3-weeks-on, 1-week-off schedule used for palbociclib and ribociclib) and higher treatment discontinuation rates with palbociclib (∼45% by 2 years in PALLAS) have been proposed as contributing factors (11,12). One plausible, yet unproven hypothesis is that more continuous CDK4/6 pathway suppression may sustain cell-cycle arrest and potentially reduce opportunities for dormant micrometastatic clones to re-enter proliferation (14). However, this explanation remains speculative, and cross-trial differences likely reflect multiple interacting factors, including baseline recurrence risk, treatment exposure (dose and duration), and discontinuation patterns (15). Additionally, monarchE and NATALEE targeted higher-risk populations on average, which may yield a larger absolute benefit. The fact that ribociclib—given intermittently but at a reduced dose (400 mg) and longer duration—was effective suggests that dose intensity and exposure duration are key factors. These nuances highlight that not all CDK4/6 inhibitors are interchangeable in the adjuvant setting. Clinicians must rely on the agents and regimens proven in trials (currently abemaciclib 2 years or ribociclib 3 years) for high-risk patients, rather than extrapolate results from metastatic use or from one CDK4/6 inhibitor to another.

Implications for clinical practice and policy

The confirmation of OS benefit with adjuvant abemaciclib reinforces escalation for appropriately selected high-risk HR⁺/HER2⁻ disease, but it also increases real-world complexity when multiple effective agents apply to the same patient. In the absence of head-to-head sequencing data, a practical approach is to frame decisions as scenario-based and preference-sensitive rather than prescriptive. For example, in a germline BRCA1/2-mutated, high-risk HR⁺/HER2⁻ patient eligible for OlympiA, one possible approach is to complete local therapy and (neo)adjuvant chemotherapy, deliver 1 year of adjuvant olaparib (with ET when indicated), and then consider adjuvant CDK4/6 inhibition afterward on an individualized basis—explicitly acknowledging that direct comparative sequencing evidence is lacking and combination is often impractical due to overlapping tolerability concerns (e.g., myelosuppression). After completing 2 years of adjuvant abemaciclib, current evidence supports continuation of standard ET; the optimal role of additional targeted endocrine agents after prior CDK4/6 exposure in the early-stage setting remains an unanswered question. In a “post-monarchE” landscape, adjuvant CDK4/6 inhibition may function as a backbone for selected patients, while next-generation ER-targeting agents may become partners or successors as evidence matures. For example, vepdegestrant (ARV-471), a PROTAC-based ER degrader (16), and palazestrant (OP-1250), a next-generation orally bioavailable SERD (17), are being investigated in advanced ER⁺/HER2⁻ breast cancer. These agents aim to achieve deeper ER suppression than conventional endocrine therapies. Although several studies have explored combinations with CDK4/6 inhibitors, the optimal integration of next-generation ER degraders within CDK4/6-based treatment paradigms remains to be defined, particularly in the early-stage setting, where dedicated adjuvant trials will be required.

In the future, giredestrant may be introduced for adjuvant use. If CDK4/6 inhibitors or olaparib are used initially, giredestrant may be deployed during subsequent AI or tamoxifen monotherapy phases.

These advances raise health-economic and access questions. In resource-constrained settings, prioritization may reasonably favor therapies with demonstrated OS benefit when available, or those with the largest expected absolute benefit in clearly defined high-risk groups, supported by biomarker/risk enrichment to reduce overtreatment. Where access to high-cost agents is limited, optimized ET (including generics) and regionally feasible, evidence-based options (e.g., S-1 in settings where it is available and supported by trial data) may offer pragmatic alternatives, while acknowledging that cross-regional generalizability can vary.

Finally, long-term follow-up is vital. HR⁺ breast cancer carries relapse risk up to 10–20 years. Further OS data from NATALEE or results from oral SERD trials like EMBER-4 (imlunestrant) or other trials will clarify durability and safety (Table 2). Encouragingly, no late toxicities have emerged; olaparib has not increased MDS/AML risk with extended follow-up.

Conclusions

In summary, the adjuvant therapy landscape for HR⁺/HER2⁻ breast cancer is evolving rapidly, driven by positive trial results that extend beyond improved disease-free survival to improved OS. The monarchE trial’s OS benefit with abemaciclib validates the strategy of escalation for patients with the highest risk, offering them a better chance at cure. Parallel successes—ribociclib in NATALEE showing robust iDFS gains, olaparib in OlympiA confirming long-term survival benefit in BRCA-mutated patients, the novel SERD giredestrant in lidERA demonstrating superiority to standard ET, and the Japanese POTENT study adding oral chemotherapy—all point to meaningful reductions in recurrence for different high-risk cohorts. As clinicians integrate these findings, multidisciplinary planning (medical oncology, surgery, genetics, and survivorship care) will be essential to navigate the more complex adjuvant regimens now available. Ultimately, the progress seen recently gives new hope that more patients with early breast cancer will live longer, disease-free lives thanks to the judicious addition of these targeted therapies on top of endocrine treatment. The challenge ahead will be to optimize the use of these therapies, getting the right treatment to the right patient, while maintaining quality of life and access to care globally.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-2026-1-0004/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-2026-1-0004/coif). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Rastogi P, O'Shaughnessy J, Martin M, et al. Adjuvant Abemaciclib Plus Endocrine Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative, High-Risk Early Breast Cancer: Results From a Preplanned monarchE Overall Survival Interim Analysis, Including 5-Year Efficacy Outcomes. J Clin Oncol 2024;42:987-93. [Crossref] [PubMed]
2. Johnston S, Martin M, O'Shaughnessy J, et al. Overall survival with abemaciclib in early breast cancer. Ann Oncol 2026;37:155-65. [Crossref] [PubMed]
3. Slamon DJ, Fasching PA, Hurvitz S, et al. Rationale and trial design of NATALEE: a Phase III trial of adjuvant ribociclib + endocrine therapy versus endocrine therapy alone in patients with HR+/HER2- early breast cancer. Ther Adv Med Oncol 2023;15:17588359231178125. [Crossref] [PubMed]
4. Hortobagyi GN, Lacko A, Sohn J, et al. A phase III trial of adjuvant ribociclib plus endocrine therapy versus endocrine therapy alone in patients with HR-positive/HER2-negative early breast cancer: final invasive disease-free survival results from the NATALEE trial. Ann Oncol 2025;36:149-57. [Crossref] [PubMed]
5. Crown J, Stroyakovskii D, Yardley DA, et al. Adjuvant ribociclib plus nonsteroidal aromatase inhibitor therapy in patients with HR-positive/HER2-negative early breast cancer: 5-year follow-up of NATALEE efficacy outcomes and updated overall survival. ESMO Open 2025;10:105858. [Crossref] [PubMed]
6. Geyer CE Jr, Garber JE, Gelber RD, et al. Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer. Ann Oncol 2022;33:1250-68. [Crossref] [PubMed]
7. Garber J, Cameron D, Campbell C, et al. Abstract GS1-09: OlympiA: A phase 3, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients w/ germline BRCA1 & BRCA2 pathogenic variants & highrisk HER2-negative primary breast cancer. Clin Cancer Res 2025;31:GS1-09. [Crossref]
8. Bardia A, Bidard FC, Blok EJ, et al. Abstract GS1-10: Giredestrant vs standard-of-care endocrine therapy as adjuvant treatment for patients with estrogen receptor-positive, HER2-negative early breast cancer: results from the global phase III lidERA Breast Cancer trial. Clin Cancer Res 2026;32:GS1-10. [Crossref]
9. Toi M, Imoto S, Ishida T, et al. Adjuvant S-1 plus endocrine therapy for oestrogen receptor-positive, HER2-negative, primary breast cancer: a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol 2021;22:74-84. [Crossref] [PubMed]
10. Takada M, Saji S, Ueno T, et al. Adjuvant S-1 plus endocrine therapy for ER-positive, HER2-negative, primary breast cancer: post-POTENT trial prognostic survey. NPJ Breast Cancer 2025;11:113. [Crossref] [PubMed]
11. Gnant M, Dueck AC, Frantal S, et al. Adjuvant Palbociclib for Early Breast Cancer: The PALLAS Trial Results (ABCSG-42/AFT-05/BIG-14-03). J Clin Oncol 2022;40:282-93. [Crossref] [PubMed]
12. Mayer EL, Hlauschek D, Gnant M, et al. Palbociclib with adjuvant endocrine therapy in early breast cancer: 5-year follow-up analysis of the global multicenter, open-label, randomized phase III PALLAS trial (ABCSG-42/AFT-05/PrE0109/BIG-14-13). Ann Oncol 2026;37:271-7. [Crossref] [PubMed]
13. Loibl S, Marmé F, Martin M, et al. Palbociclib for Residual High-Risk Invasive HR-Positive and HER2-Negative Early Breast Cancer-The Penelope-B Trial. J Clin Oncol 2021;39:1518-30. [Crossref] [PubMed]
14. Goel S, DeCristo MJ, McAllister SS, et al. CDK4/6 Inhibition in Cancer: Beyond Cell Cycle Arrest. Trends Cell Biol 2018;28:911-25. [Crossref] [PubMed]
15. Lobo-Martins S, Luen SJ, Piccart M, et al. Tailoring targeted therapies for younger women with ER-positive early-stage breast cancer. Nat Rev Clin Oncol 2026;23:297-315. [Crossref] [PubMed]
16. Campone M, De Laurentiis M, Jhaveri K, et al. Vepdegestrant, a PROTAC Estrogen Receptor Degrader, in Advanced Breast Cancer. N Engl J Med 2025;393:556-68. [Crossref] [PubMed]
17. Hamilton EP, Patel MR, Borges VF, et al. Palazestrant, a novel oral Complete Estrogen Receptor Antagonist (CERAN) and Selective Estrogen Receptor Degrader (SERD), in patients with ER+/HER2- advanced or metastatic breast cancer: phase 1/2 study results. Breast Cancer Res 2025;27:119. [Crossref] [PubMed]