FormalPara Key Summary Points

Abemaciclib is approved for treatment of high-risk hormone receptor-positive, HER2-negative early breast cancer in the adjuvant setting.

Adjuvant ribociclib improves invasive disease-free survival of patient with stage II–III, hormone receptor-positive/HER2-negative breast cancer.

Both abemaciclib and ribociclib increase the chance of curing patients with hormone receptor-positive/HER2-negative early breast cancer.

The choice between abemaciclib and ribociclib will depend on regulatory approval, drug access, costs, risk of recurrence, long-term efficacy, safety profile, and patient preferences.

Introduction

Breast cancer is the most common malignancy diagnosed in women worldwide, and hormone receptor-positive/HER2 (also known as ERBB2)-negative is the most common subtype, accounting for approximately 70% of all diagnoses [1]. Most cases are diagnosed at an early stage, thus being potentially curable with locoregional and systemic treatments. However, up to 20% of patients relapse in the first 10 years from diagnosis, with either locoregional or distant recurrences that are, in the latter case, incurable [2]. Therefore, research efforts have been focusing on testing new treatment strategies to reduce the risk of recurrence in these patients.

CDK4/6 inhibitors represent a cornerstone in the treatment of breast cancer. In the metastatic setting, three CDK4/6 inhibitors (i.e., palbociclib, ribociclib, abemaciclib) are approved, in combination with endocrine therapy, as standard of care in first-line treatment and a possible treatment option in later lines [3]. In the early setting, one CDK4/6 inhibitor (i.e., abemaciclib) has been approved as adjuvant treatment for patients with hormone receptor-positive/HER2-negative early breast cancer at high risk of recurrence [4].

Conversely, two trials testing the addition of adjuvant palbociclib did not demonstrate a benefit over standard endocrine therapy and, therefore, palbociclib is not approved with this indication to date. The PALLAS trial [5] evaluated the addition of palbociclib in the adjuvant setting for 2 years, and showed no improvement in invasive disease-free survival (iDFS) when compared to standard endocrine therapy. Also the PENELOPE-B trial [6], testing the addition of 1 year of palbociclib to endocrine therapy in patients with residual disease after the completion of neoadjuvant chemotherapy, did not demonstrate a benefit in terms of iDFS, its primary endpoint.

Yet the current treatment landscape is constantly subject to challenge as soon as the results of key ongoing trials become available.

At the ASCO Annual Meeting 2023, primary results from the NATALEE trial were presented (Table 1) [7]. NATALEE is a randomized, phase III trial testing ribociclib and endocrine therapy as adjuvant treatment in patients with stage II–III, hormone receptor-positive/HER2-negative breast cancer; in total, 5101 patients were randomized to receive either ribociclib (400 mg/day; 3 weeks on/1 week off for 3 years) in combination with endocrine therapy (letrozole 2.5 mg/day or anastrozole 1 mg/day ± goserelin, for at least 5 years) or endocrine therapy alone. After a median follow-up of 34 months, ribociclib was associated with a longer iDFS (3-year iDFS rates 90.4% vs. 87.1%, hazard ratio (HR) 0.75; 95% CI, 0.62–0.91; p = 0.0014). iDFS benefit was consistent across subgroups. Secondary endpoints of overall survival, recurrence-free survival, and distant disease-free survival were also consistently improved in the ribociclib arm, although the data are not mature enough to be considered as conclusive.

Table 1 Main characteristics of study population and outcomes of MonarchE and NATALEE trials
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Results from NATALEE were not surprising if we consider the consistent benefit in survival observed in all clinical trials testing ribociclib in the metastatic setting including in the endocrine-resistant population [8,9,10,11].

The results of NATALEE challenge the position of adjuvant abemaciclib in the treatment algorithm for early breast cancer. Abemaciclib was approved on the basis of the results of MonarchE trial (Table 1) [12]. MonarchE is a randomized, phase III trial testing adjuvant abemaciclib in patients with high-risk hormone receptor-positive/HER2-negative early breast cancer; in total, 5637 patients were randomized to receive abemaciclib (150 mg orally twice a day for 2 years) plus endocrine therapy or endocrine therapy alone. At a median follow-up of 42 months, abemaciclib was associated with longer iDFS (HR 0.66, 95% CI 0.58–0.76) and distant relapse-free survival (HR 0.66, 95% CI 0.57–0.77) (Table 1).

The partially overlapping indications of the two CDK4/6 inhibitors (Fig. 1) justify a scientific debate on how to wisely choose the best adjuvant CDK4/6 inhibitor for early breast cancer.

Fig. 1
figure 1

Potential candidates for adjuvant CDK4/6 inhibitors on the basis of eligibility criteria of MonarchE and NATALEE trials. The green cells represent eligibility, while the red cells represent non-eligibility. *Based on eligibility criteria in clinical trials

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Which Adjuvant CDK4/6 Inhibitor for Which Patient?

Assuming that ribociclib will be approved in the adjuvant setting on the basis of the recent findings from NATALEE, some preliminary questions should be addressed to wisely choose the best CDK4/6 inhibitor for each patient: (1) Who will benefit from the treatment? (2) How much drug is needed for patients to benefit? (3) What are the potential downsides in terms of safety and tolerability?

Concerning the first question, there are important differences in terms of patient selection between NATALEE and MonarchE trials (Fig. 1). In the early setting, both tumor burden and disease biology are well-established risk factors for disease recurrence. Patients with nodal involvement [13] and/or high-risk gene expression test results [14,15,16] have the highest risk of disease recurrence, despite optimal treatment with (neo)adjuvant chemo-endocrine therapy. In MonarchE, only patients with node-positive disease were eligible; the definition of “high risk” consisted in either 4 or more positive lymph nodes, or 1–3 positive lymph nodes with either grade 3 disease or tumor size ≥ 5 cm. A smaller group of patients were enrolled with 1–3 positive axillary lymph nodes and Ki-67 ≥ 20%. In NATALEE, all patients with stage II–III tumors were eligible, except for stage IIA that, to be eligible, should have either 1–3 positive lymph nodes or, if node-negative, some additional risk factors (grade 3, or grade 2 with Ki-67 ≥ 20%, or high genomic risk) (Fig. 2). This means that the population of MonarchE was at “higher risk” of recurrence compared to the population of NATALEE, which included a broader range of tumors, including node-negative ones.

Fig. 2
figure 2

Differences between adjuvant abemaciclib and ribociclib. FDA Food and Drug Administration, EMA European Medicine Agency, HR+ hormone receptor-positive, EBC early breast cancer, AEs adverse events

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Treatment duration was also different in the two studies. In MonarchE, abemaciclib was administered for 2 years, while in NATALEE, ribociclib was administered for 3 years. If, on the one hand, a longer duration retains the potential rationale of prolonging cell cycle arrest and driving more tumor cells into irreversible senescence [17,18,19], the possible implications of extended duration on toxicity, treatment adherence, and financial sustainability should also be considered.

Interestingly, in NATALEE, ribociclib was administered at a lower dosage compared to the one used in the metastatic setting (400 vs. 600 mg/daily) [7]. This choice was mainly meant to improve tolerability, while maintaining efficacy. Of note, the AMALEE trial [20] demonstrated a more favorable safety profile of the lower dosage for adverse events that are concentration dependent (i.e., QT prolongation and neutropenia). However, it failed in showing non-inferiority in terms of overall response rate (primary endpoint) (47.5% vs. 55.2%, ratio 0.86, 95% CI 0.73–1.02), although median progression-free survival (secondary endpoint) was very similar between the two cohorts (24.9 vs. 25.1 months; HR 1.07, 95% CI 0.78–1.46).

Despite the lower dosage in NATALEE, 19% of patients had to discontinue ribociclib as a result of adverse events, while only 4% of patients discontinued the aromatase inhibitor in the control arm [7]. In MonarchE, early discontinuation of abemaciclib due to adverse events occurred in 18.5% of patients [21], and 6% of patients discontinued both abemaciclib and endocrine therapy as a result of adverse events [12]. Safety, tolerability, dose management, and treatment adherence require close attention when broadening the spectrum of adjuvant therapy for more years. At ASCO 2023, an analysis of MonarchE efficacy and safety data according to age was presented [22]. Older patients (i.e., > 65 years old) were shown to derive the same benefit from the addition of abemaciclib to adjuvant endocrine therapy (iDFS, distant relapse-free survival), but to experience treatment discontinuations and dose reductions more frequently. Importantly, the benefit of abemaciclib was maintained when dose modifications were undertaken to manage adverse events; these findings underline the importance of strictly following these patients to ensure an optimal treatment tolerance and adherence.

Concerning the efficacy results, in NATALEE 3-year iDFS was longer with ribociclib compared to endocrine therapy alone; however, little can be said of what happens after 3 years, because of the very low number of patients at the tails of the curves, suggesting that longer follow-up is needed, and considering that at the time of this analysis, the percentage of patients completing 3 years of ribociclib was only approximately 20% (n = 515), thus reinforcing the concept that these are early, and not yet mature, data [7]. In the subgroup analysis, the benefit from the addition of ribociclib seems to be consistent in all subsets of patients, including those with node-negative disease [7]. Notably, the low number of events in this subgroup and the large confidence interval require caution when interpreting these results. Indeed, despite some HR < 1 in some subgroups, some of those confidence intervals cross 1, such as in the low-risk patient population (e.g., node-negative, grade I tumors, no previous chemotherapy, Ki-67 ≤ 20%, stage II disease), and longer follow-up in this trial is crucial.

In MonarchE, the efficacy of abemaciclib is confirmed by a longer follow-up and more mature, reassuring data, showing that iDFS and distant-disease free survival persist and deepen beyond completion of 2-years abemaciclib treatment period. At 4 years, absolute difference was 6.4%, HR 0.66, 95% CI 0.58–0.76 for iDFS, and 5.9%, HR 0.66, 95% CI 0.57–0.77 for distant disease relapse-free survival [12]. At the last ESMO congress, 5-year efficacy results were presented: with a median follow-up of 4.5 years (54 months), the benefit of abemaciclib was sustained with an increase in absolute iDFS and distant relapse-free survival of 7.6% and 6.7%, respectively [23]. Overall survival data were not yet mature at the last ESMO 2023 update; however, at interim analysis 3, 208 patients in the abemaciclib arm and 234 patients in the control group had an overall survival event (HR 0.903, 95% CI 0.749–1.088; p = 0.284), and at the same date the patients who are alive with metastatic disease numbered 138 in the abemaciclib arm and 269 in the control arm. Although not statistically significant, these numbers seem to suggest an initial benefit also in terms of overall survival, although longer follow-up is needed to draw definitive conclusions.

The magnitude of benefit from the addition of abemaciclib and of ribociclib cannot be compared, as the two studies included populations with different risk of relapse, which hampers cross-trial comparisons. A pooled analysis at a later stage with more mature data could be helpful to address some of the existing questions on this debated topic. However, it is worth noting that at median follow-up of 27 months in MonarchE (similar to the one in NATALEE analysis), the magnitude of benefit for abemaciclib was 5.4% for iDFS and 4.2% for distant relapse-free survival [24].

Importantly, hormone receptor-positive/HER2-negative breast cancer retains a risk of recurrence that persists for several years after diagnosis [13, 25]. Therefore, both NATALEE and MonarchE require a longer follow-up, not only for efficacy beyond treatment period and overall survival results but also for safety and patient-reported outcomes (PROs). PROs are available for MonarchE and showed no detrimental effect of abemaciclib in quality of life [21]. PROs from NATALEE are not yet available.

Concerning the quality of life and survivorship issues, it must also be reminded that, to date, there is limited data on the gonadotoxicity of CDK4/6 inhibitors, and this is an issue that needs to be considered in premenopausal patients who want to complete their family plan after treatment for hormone receptor-positive breast cancer [26]. Indeed, thanks to data from the recently published POSITIVE trial [27] we know that it may be considered safe to temporarily interrupt adjuvant endocrine therapy to try to achieve pregnancy; however, in the POSITIVE study no data regarding the issue of possible interruption of CDK4/6 inhibitors were available, and we do not know whether their previous treatment may worsen fertility outcomes in younger patients [28]. All these aspects must be discussed during oncofertility counselling before starting adjuvant endocrine treatment in combination with CDK4/6 inhibitors. Also, POSITIVE had a lower-risk patient population (46% stage I and 47% stage II disease) and, therefore, extrapolating that data to this more high-risk population is not advised.

After the positive results of MonarchE and NATALEE, one might wonder whether there is still need for (neo)adjuvant chemotherapy for patients with hormone receptor-positive/HER2-negative early breast cancer. It is important to consider that these studies do not help address this question. Almost the totality of patients enrolled in both studies had received prior chemotherapy (88% in NATALEE, and 95.5% in MonarchE). This question will be better answered by other ongoing trials. The ongoing WSG ADAPTcycle trial [29] is randomizing patients with hormone receptor-positive/HER2-negative early breast cancer with uncertain chemotherapy benefit (i.e., intermediate risk) to either adjuvant ribociclib plus endocrine therapy or adjuvant chemotherapy followed by endocrine therapy.

Interestingly, in MonarchE prior chemotherapy (neoadjuvant vs. adjuvant vs. none) was a stratification factor and a prespecified exploratory analysis of patients who received neoadjuvant chemotherapy confirmed iDFS and distant relapse-free survival benefit from the addition of adjuvant abemaciclib [30].

Several trials on CDK4/6 inhibitors for early breast cancer are ongoing, and will help individualize treatment decision in early breast cancer in the next future (e.g., NCT04565054, NCT04584853).

Another important issue is that neither MonarchE nor NATALEE tested BRCA1/2 mutation in their patients and, today, these high-risk patients with BRCA1 or BRAC2 mutations are candidates to receive adjuvant olaparib on the basis of the Olympia trial [31, 32].

Conclusions

Both abemaciclib and ribociclib increase the chance of curing patients with hormone receptor-positive/HER2-negative breast cancer, with an acceptable safety profile. After the positive results of MonarchE and NATALEE trials, the proportion of patients who are potentially eligible for adjuvant CDK4/6 inhibitors is broad; the choice between abemaciclib and ribociclib will depend on regulatory approval, drug access, costs, risk of recurrence, long-term efficacy, safety profile, and patient preferences (especially on safety profile and on treatment duration). Furthermore, the use of CDK4/6 inhibitors in the early setting raises questions in the metastatic setting. The degree of antitumor activity of CDK4/6 inhibitors after CDK4/6 inhibitors is still uncertain, and much needs to be learnt on the sequencing of each CDK4/6 inhibitor after the other.