The Butterfly Effect: Escalating Adjuvant Endocrine Therapy with monarchE

Allison Butts, PharmD, BCOP
Clinical Coordinator, Oncology Pharmacy; Director,
PGY2 Oncology Residency Program,
UK HealthCare- Markey Cancer Center,
Lexington, KY

Hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer represents nearly 70% of breast cancer cases, the vast majority of which are diagnosed in early stages. The 5-year relative survival for this cohort of patients exceeds 94% when all stages are considered together. However, this figure drops from 100% for localized disease at presentation to 89.9% with regional disease, and further to 30.6% for metastatic disease.¹ In addition to surgery +/- radiation, treatment of early-stage HR+ breast cancer varies by stage and may include chemotherapy plus endocrine therapy, or endocrine therapy alone (aromatase inhibitors or tamoxifen, +/- ovarian suppression). Adjuvant bisphosphonate therapy may also be added to reduce the risk of bone recurrence for high-risk patients.²

Meaningful data have been published to guide treatment selection based on risk of recurrence for early-stage HR+ breast cancer patients. The TAILORx trial validated the use of the 21-gene breast cancer assay, Oncotype DX®, to predict chemotherapy benefit based on recurrence risk score in HR+, lymph node negative patients.³ RxPONDER followed, which demonstrated a similar ability to predict chemotherapy benefit using the Oncotype recurrence score in patients with one to three positive lymph nodes.⁴ The MINDACT trial provided data on the use of the 70-gene signature test, MammaPrint®, as a tool to tailor treatment plans for patients with early-stage HR+ with up to three positive lymph nodes.⁵ Together, these clinical trials have reduced the amount of chemotherapy that is administered to patients with low-risk HR+ breast cancer, while maintaining favorable disease recurrence and survival outcomes.

Unfortunately, about 20% of patients treated with adjuvant endocrine therapy will develop a breast cancer recurrence within 10 years.⁶ As a result, much work is being done to identify approaches to enhance or escalate treatment of high-risk HR+ breast cancer. Addition of a CDK4/6 inhibitor to adjuvant endocrine therapy has been investigated in three key trials: PALLAS, PENELOPE-B, and monarchE.

CDK4/6 inhibitors are a mainstay in the treatment of metastatic HR+ breast cancer.² Upon binding of estrogen to the estrogen receptor, cyclin D1 expression is increased, along with activation of cyclin-dependent kinases, ultimately resulting in phosphorylation of the retinoblastoma protein (pRb).⁷ CDK4 and CDK6, in complex with cyclin D, drive cell progression from the G1 to S phase. Therefore, CKD4 and CDK6 are attractive drug targets due to the ability to arrest the cell cycle and block cell growth.⁸

The phase 3 PALLAS trial randomized patients with stage 2 or 3 HR+ breast cancer (n=5760) to receive palbociclib for 2 years in addition to 5-10 years of endocrine therapy, or endocrine therapy alone for 5-10 years. At the time of the final analysis, 4-year invasive disease-free survival (IDFS) was 84.2% in the palbociclib group and 84.5% in the control group (p=0.65).⁹ The phase 3 PENELOPE-B trial enrolled high-risk HR+ patients with residual disease after neoadjuvant chemotherapy (n=1250). Patients were treated with palbociclib for 1 year in addition to 5-10 years of endocrine therapy, or endocrine therapy alone. No difference was seen between the groups at 4 years for IDFS (73% vs. 72.4%, p=0.53).¹⁰

Recently, the phase 3 monarchE trial randomized high-risk HR+ patients (n=5637) to 2 years of abemaciclib in addition to 5-10 years of endocrine therapy, or endocrine therapy alone. To be included, patients had to have at least four positive lymph nodes or one to three positive nodes with one of the following additional risk factors: tumor size ≥5 cm or grade 3 histology (Cohort 1), or one to three positive nodes and Ki-67 ≥ 20% (Cohort 2). Patients may have received up to 12 weeks of endocrine therapy prior to randomization. Radiation, adjuvant, and neoadjuvant chemotherapy was received in 95.4%, 58.3%, and 37.0% of the study population, respectively. Patients were of a median age of 51.0 years and the majority were post-menopausal at diagnosis (56.5%). Aromatase inhibitors were the most commonly prescribed endocrine therapy (68.3%, including 14.2% treated concurrently with ovarian suppression).¹¹

Unlike PALLAS and PENELOPE-B, monarchE reported a benefit in invasive disease-free survival (IDFS). At 2 years, addition of abemaciclib improved IDFS from 89.3% to 92.3% (p=0.0009) in the intent-to-treat population. Furthermore, distant recurrence-free survival (DRFS) was increased from 90.8% to 93.8% (p=0.0009).¹² This benefit was maintained at 3 years for both IDFS (88.8% vs. 83.4%, p<0.0001) and DRFS (86.1% vs 90.3%, p<0.0001). When patients in Cohort 1 were stratified based on Ki-67 index, those who were Ki-67-high had an absolute benefit in 3-year IDFS of 7.1% (HR 0.63, 91% CI 0.49-0.80). In contrast, patients in Cohort 1 with a low Ki-67 index demonstrated a less pronounced absolute benefit of 4.5% (HR 0.70, 91% CI 0.51-0.98). While both subsets of patients derived a benefit from abemaciclib, the magnitude of benefit was reduced based on this biomarker.¹³ Based on the results of the monarchE trial, the FDA approved abemaciclib, in combination with endocrine therapy, for the adjuvant treatment of adult patients with HR+, node-positive, early breast cancer at high risk of recurrence and a Ki-67 score ≥20% on October 12, 2021. The Ki-67 IHC MIB-1 pharmDx assay was approved as a companion diagnostic.¹⁴ Notably, the FDA-approved indication may expand pending additional follow-up data such as overall survival in the intent-to-treat population.

There are several potential explanations for the discordant results between these three trials. First, the definition of “high-risk” was variable between trials and may have skewed the efficacy results. The duration of adjuvant CDK4/6 inhibition notably varied from 2 years in PALLAS and monarchE to 1 year in Penelope-B. The phase 3 NATALEE trial is ongoing, which will explore the activity of 3 years of ribociclib in the adjuvant setting, possibly providing more clarity on this issue.¹⁵ Next, the discontinuation rates varied between trials, with 27.7% of patients discontinuing abemaciclib early in monarchE, and 42% and 20% discontinuing palbociclib in PALLAS and PENELOPE-B, respectively.^9,10,12 Lastly, the duration of follow-up differed between studies. Importantly, the improvement in IDFS observed in PENELOPE-B declined over time, with a 4.3% improvement at 2 years, 3.5% at 3 years, and 0.6% 4 years.¹⁰ The authors of monarchE have demonstrated sustained results from 2 to 3 years but longer follow-up is needed for each of these landmark trials.

The landscape of treatment options for HR+ breast cancer is continually evolving as we learn more about opportunities to tailor treatments based on risk stratification. De-escalation of therapy in low-risk early-stage disease using genomic assays is now commonplace in clinical practice. Identifying high-risk patients for escalation of therapy is now a major focus area for clinical research. The monarchE data supports incorporating 2 years of adjuvant abemaciclib therapy in select high-risk patients, making abemaciclib the first drug to receive FDA-approval for adjuvant hormone-receptor positive breast cancer in over 15 years.¹⁴ However, conflicting results from other large studies should not be ignored and require critical evaluation.

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