IMPlementing geriatric assessment for dose Optimization of CDK 4/6-inhibitors in older bReasT cAncer patieNTs

Current evidence from both randomized trials and real-world evidence studies suggests that older breast cancer patients derive clinical benefits from the addition of CDK4/6 inhibitors to endocrine therapy but with higher risk for adverse events and treatment discontinuation compared to younger patients. The IMPORTANT project is a pragmatic clinical study with decentralised approach for older patients aged more than 70 years old with advanced hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer, not amenable for curative treatment and without prior therapy for advanced disease, who are suitable to receive CDK4/6 inhibitors plus endocrine therapy as first line therapy. The study implements two approaches with high level of evidence, namely the use of comprehensive geriatric assessment (CGA) approach in treatment decision making and the use of CDK4/6 inhibitors as the initial treatment of choice, to investigate whether a common clinical practice (starting dose reduction of CDK4/6 inhibitors in older patients) with evidence of low certainty can be standardized using a more individualized-based approach. The IMPORTANT trial will be recruiting patients from six European countries: Sweden; Finland; Norway; Italy; Spain; and Greece. The trial will include 495 female and male patients. The project will also perform a series of analyses over a) a wide range of clinical-relevant primary and secondary endpoints targeting to contribute to current clinical practice and b) the implementation of specific strategies aiming at more individualized treatment and follow-up approaches to a clinical trial setting that highly resembles real-world setting due to the trial's pragmatic design.

The project duration is 60 months involving a competitive consortium of 19 partners from 11 countries, which corresponds to a well-balanced structure, involving clinical sites, SMEs, universities and patient advocacy organizations. Despite the great diversity of entities within the proposal, IMPORTANT partners bring state-of-the-art complementary skills ensuring the ability of the consortium to successfully complete the proposed work.This action is part of the Cancer Mission cluster of projects on ‘Diagnosis and Treatment’.

During the first reporting period, the consortium designed a pragmatic, randomized controlled clinical trial specifically tailored for older patients with advanced breast cancer. The trial incorporates all innovative aspects outlined in the project objectives, including implementation of a comprehensive geriatric assessment (CGA); study outcomes relevant to older patients; an adaptive approach to study design, and a decentralized trial approach.
A study protocol, patient information and informed consent forms were developed during this period, and regulatory approval was obtained for clinical sites in six European countries: Finland, Greece, Italy, Norway, Spain, and Sweden. Patient recruitment began in April 2024, with participants currently being enrolled from four of these countries. Study initiation in Greece and Italy is pending but expected to commence shortly.
All technical solutions required for study execution have been evaluated for security and privacy aspects and implemented at all study sites. Additionally, all committees necessary for the project's lifecycle have been established and are actively working to ensure the project's smooth progress.

The results of the IMPORTANT study are anticipated following the completion of the follow-up phase for all enrolled patients. While no preliminary results are currently available, the study has been meticulously designed to deliver outcomes that will advance the state of the art across multiple dimensions.
First, the IMPORTANT trial sets a new standard for investigating targeted therapies in older patients. It emphasizes the importance of balancing efficacy and safety, with a particular focus on quality of life (QoL) and age-related vulnerabilities. As a model for future studies for dose optimization of targeted therapies in Oncology (where a “one-size-fits-all” is the standard approach), it demonstrates how to integrate geriatric assessments and real-world outcomes into clinical trials.
Second, the trial facilitates a decentralized approach in several aspects (patient visits, collection of patient-reported outcome measures, monitoring), aiming to overcome obstacles related to the inclusion of older patients in clinical trials and the execution of pragmatic trials.
In addition, the study tracks geriatric domains—such as psychological, functional, and social health— during the patient’s cancer care journey, thus providing valuable insights into how advanced breast cancer and its treatment affect older patients. These findings are expected to inform clinical decision-making and supportive care strategies for this vulnerable group.
Finally, two innovative research pilots are planned to further enhance the scientific value of the IMPORTANT project: a digital support for recruitment and retention tool that tests the feasibility of a dedicated app to aid decision-making in trial participation and retention and an online compassion program that assesses the potential of an online self-compassion program to improve the psychological and emotional well-being of older patients participating in the trial.