Adherence and Safety of Ribociclib Plus Aromatase Inhibitors in Patients With Early Stage, HR+ and HER2- Breast Cancer (riboADHERE)

Adherence and Safety of Ribociclib Plus Aromatase Inhibitors in Patients With Early Stage, Hormonal Receptor Positive and Human Epidermal Growth Factor Receptor 2 Negative Breast Cancer

Breast cancer is the most common malignancy in women, with HR+/HER2- early breast cancer accounting for approximately 70% of cases. Although adjuvant endocrine therapy substantially reduces the risk of recurrence, a clinically meaningful proportion of patients, particularly those with intermediate- and high-risk disease, still experience relapse. The addition of CDK4/6 inhibitors such as ribociclib to endocrine therapy has demonstrated significant improvement in invasive disease-free survival (iDFS) and is now part of standard adjuvant treatment for selected patients. However, the real-world effectiveness of prolonged oral therapy depends heavily on patient adherence, which may be negatively affected by treatment duration, adverse events, and the absence of immediate perceived benefit. Evidence regarding adherence to adjuvant ribociclib therapy in routine clinical practice remains limited. This study therefore aims to evaluate whether a structured adherence-support intervention can improve treatment adherence during ribociclib therapy and to explore the relationship between adherence and long-term clinical outcomes, including iDFS.

Study Overview

• Status: Not yet recruiting
• Conditions: Breast Cancer; Adherence, Medication
• Intervention / Treatment: Behavioral: Adherence package consisting of additional education and adherence reminders

Detailed Description

Breast cancer (BC) is the most prevalent malignant tumour in women, with an estimated 2.308 million new cases and over 665,000 deaths globally in 2022. Around 90% of patients are diagnosed at an early stage and the majority of these cases, approximately 70%, are hormone receptor-positive and HER2-negative (HR+/HER2-).

Despite advancements in adjuvant endocrine therapy that significantly lower recurrence and mortality rates, 20-30 % of early-stage BC patients experience relapse within the first decade post-surgery. Around 12% of patients with HR+/HER2- BC belong to high-risk population with 5-years invasive disease-free survival (IDFS) of 70.2% vs 90.0% in non-high-risk. In the large EBCTCG meta-analysis which included 62,923 women with ER-positive early breast cancer who completed 5 years of adjuvant endocrine therapy, the risk of distant recurrence remained substantial over the subsequent 15 years and was strongly dependent on initial tumour size and nodal status.

Among patients with T1 tumours, 13-34% experienced distant recurrence during years 5-20, whereas 19-24% of those with T2 tumours relapsed over the same period, depending on nodal burden and tumour grade. These findings delineate an intermediate-risk group within HR+/HER2- early breast cancer-patients with T1-2, node-negative or limited node-positive disease-who, despite not meeting conventional "high-risk" criteria, still face a clinically meaningful long-term risk of recurrence after standard endocrine therapy. This persistent residual risk highlights the unmet need for improved risk stratification tools and additional adjuvant strategies to optimize outcomes in this intermediate-risk population.

The most recent clinically meaningful therapeutic option for these patients has been cyclin-dependent kinases 4/6 inhibitors (CDK4/6 inhibitors).

Endocrine therapy combined with CDK4/6 inhibitors (abemaciclib, palbociclib and ribociclib) is now the standard, most effective, and recommended treatment for these patients in the first or subsequent lines of treatment for advanced disease. Two CDK4/6 inhibitors, abemaciclib and ribociclib, have been assessed also for use in the adjuvant setting (MonarchE and NATALEE study). Both studies showed improvement in iDFS of combined endocrine therapy and CDK4/6 inhibitor vs endocrine therapy alone.

Ribociclib has been approved by both the FDA and EMA for patients with HR+/HER2- early breast cancer at high and intermediate risk of disease recurrence and has therefore recently been added to our current regimen for this indication in routine clinical practice.

Non-adherence to adjuvant therapy may compromise the efficacy of combined treatment in preventing disease recurrence and mortality. Some historical data report that only 60-70% of patients with early BC adhere to adjuvant therapy, making adherence a significant challenge. Key factors influencing adherence to cancer treatment include the perceived benefits of the treatment, the setting in which the treatment is administered (at home or in a hospital), the associated risks, the impact on quality of life, and the costs involved. Non-adherence often arises because patients do not experience the immediate benefits. With no visible or measurable signs of the disease and no physical symptoms of the disease, as is the case in patients receiving adjuvant treatment, and given that many would not have experienced a relapse even without adjuvant therapy, patients are much more likely to discontinue treatment if they experience adverse events/reactions (AE/AR).

Adherence to treatment with CDK4/6 inhibitors in combination with aromatase inhibitors differs from some other systemic treatments due to the continuous treatment regimen that lasts for several years without interruption. In early BC, it lasts two (abemaciclib) or three (ribociclib) years and is associated with some specific AEs. Aromatase inhibitors are associated with arthralgias, myalgias, and joint stiffness, osteopenia19-21, whereas CDK4/6 inhibitors with myelotoxicity, hepatotoxicity, cardiac toxicity and gastrointestinal symptoms.

The duration of treatment, five or more vs three years (aromatase inhibitors as monotherapy vs ribociclib in combination with aromatase inhibitors, respectively), may lead to different discontinuation rates. Despite the growing amount of real-world experiences with combined treatment with aromatase inhibitors and ribociclib in the adjuvant setting, there is currently a lack of literature specifically exploring how patient adherence and attitudes are influenced by this combination. This gap underscores the need for further research to fully understand the impact of these therapies on medication adherence.

Breast cancer is the most common malignancy among women worldwide, with HR+/HER2- early BC representing approximately 70% of cases. Despite advances in adjuvant endocrine therapy, 20-30% of patients relapse within 10 years, and high-risk subgroups have significantly lower 5-year invasive disease-free survival (iDFS) compared to non-high-risk patients6. The addition of CDK4/6 inhibitors to endocrine therapy has demonstrated clinically meaningful improvements in iDFS in large trials such as MonarchE and NATALEE. Clinically significant Overall Survival with abemacyclib in high risk early BC8 and Overall Survival trend (data immature in 2025) in high and intermediate risk early BC with ribociclib10, lead to regulatory approval of ribociclib for patients at high and intermediate risk of recurrence.

However, the effectiveness of these therapies in real-world settings depends heavily on patient adherence. Non-adherence to long-term oral therapy remains a major challenge, with historical data suggesting adherence rates as low as 60-70%. Factors influencing adherence include treatment duration, adverse events and the absence of immediate perceived benefits. Ribociclib combined with aromatase inhibitors requires continuous administration for up to three years and is associated with specific adverse events such as neutropenia, ALT/AST elevations, QTc prolongation, fatigue, alopecia which may further impact adherence.

Currently, there is limited evidence on adherence patterns and patient attitudes toward combined ribociclib and endocrine therapy in the adjuvant setting. This gap underscores the need for research to evaluate whether structured adherence-support interventions can improve medication adherence and potentially influence clinical outcomes like iDFS. Understanding these relationships will inform strategies to optimize real-world effectiveness of CDK4/6 inhibitor ribociclib therapy.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Neza Gros; Phone Number: +386 1 5879 014; Email: ngros@onko-i.si

Study Locations

• Slovenia
  • Ljubljana, Slovenia, 1000
    • Institute of Oncology Ljubljana

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Female or male patient prescribed with ribociclib in combination with an aromatase inhibitor independently of trial participation
• Patient was prescribed ribociclib independently of this trial protocol and has not yet started cycle 1
• Patient is ≥ 18 years-old at the time of ICF signature
• Patient has mandatory Slovenian health insurance
• Patient understands and speaks Slovenian language and is of congitive capability to participate in the trial
• Patient has access to phone
• Patient voluntarily agrees to participate in the trial and provides written ICF

Exclusion Criteria:

• Patient is not treated with the combination of ribociclib and aromatase inhibitor for Early BC
• Metastatic Hormone Receptor positive and HER2- negative BC
• Any medical condition that, in the opinion of the investigator, would interfere with adherence participation in the trial (i.e. significant cognitive impairment, psychiatric condition)
• Language barrier that precludes informed consent or meaningful participation in the adherence intervention

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention arm: structured adherence-support package; structured adherence-support package consisting of scheduled reminders, structured educational reinforcement discussion and materials delivered at enrolment and reinforced at specified intervals	Behavioral: Adherence package consisting of additional education and adherence reminders; Adherence package consisting of additional education and adherence reminders
No Intervention: Control arm: usual care according to local practice; Control arm: usual care according to local practice (no additional adherence package).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of days covered (PDC)	The primary objective is to show that a structured adherence package increases mean adherence, expressed as days_taken/days_prescribed. To maintain comparability with previous studies, we will use the independent samples t test with alpha=0.05 to compare the means between groups. H0: there is no difference in mean PDC between groups (SoC + behavioural intervention vs SoC)	Randomization to end of treatment with ribociclib: 3 years from enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
iDFS	estimate invasive disease free survival (iDFS) in both treatment groups	5 years form randomization
5-year survival	estimate association between adherence and survival	5 years form randomization

Collaborators and Investigators

• Sponsor: Institute of Oncology Ljubljana

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): September 1, 2029
• Study Completion (Estimated): September 1, 2032

Study Registration Dates

• First Submitted: May 20, 2026
• First Submitted That Met QC Criteria: June 3, 2026
• First Posted (Actual): June 5, 2026

Study Record Updates

• Last Update Posted (Actual): June 5, 2026
• Last Update Submitted That Met QC Criteria: June 3, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: HR+; HER2-; Early breast cancer; CDK4/6 adherence
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Behavior; Skin and Connective Tissue Diseases; Treatment Adherence and Compliance; Health Behavior; Patient Compliance; Patient Acceptance of Health Care; Breast Neoplasms; Medication Adherence
• Other Study ID Numbers: ORI2026-20

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No