Treatment options in ER+/HER2- BC patients post first line CDK4/6 inhibition

Prof François Duhoux from the Cliniques Universitaires Saint Luc (B) and Dr Carlos Barrios from the São Lucas Hospital in Brazil discuss the crucial question of whether endocrine monotherapy remains effective after CDK4/6 inhibition.

They highlight the historical uniformity in therapeutic approaches, while recent insights into biological diversity among patients challenge the simplistic assumption of uniform responses. The complexity of cancer restricts the efficacy of single-agent therapy, promoting the likelihood of combination drug regimens. The post-CDK4/6 inhibition strategy requires precise patient profiling. Establishing clinical biomarkers, including PI3K, AKT, BRCA1, and co-mutations, is crucial for identifying specific scenarios and designing targeted trials. The experts advocate a comprehensive approach involving clinical and molecular biomarkers, coupled with diverse drugs. Biomarker assessments, timed according to disease status, provide insights into clonal nature, treatment response, and progression. This integrated approach aims to enhance the precision and efficacy of therapeutic interventions.

Beyond biomarker-driven treatment algorithms, the question arises regarding the continued use of CDK4/6 inhibitors. Definitive evidence that changing the cyclin inhibitor may enhance efficacy compared to the persistence of the same drug is currently lacking, discouraging this as a routine approach in clinical practice. Several trials are exploring the strategy of maintaining cyclin inhibition while altering the hormonal agent as a foundational component.

The experts underscore the significance of the PI3K pathway in resistance mechanisms and co-signalling interactions in cancer cells. So in addition to hormonal agents like SERDs and ongoing CDK4/6 inhibition, PI3K inhibitors play a crucial role. Although alpelisib has shown efficacy, concerns arise due to its adverse safety profile. Other PI3K inhibitors present promise with improved effectiveness and reduced toxicity. A strategic approach involves simultaneous blockade of various pathways, presenting a potential trade-off between increased efficacy and heightened toxicity. It is essential not to overlook conventional drugs like everolimus, which, when combined with other endocrine agents, serves as a robust backbone, showing significant promise in diverse combinations.

Patients with BRCA1 or BRCA2 germline mutations can benefit from PARP inhibitors beyond traditional endocrine therapies. Relying solely on NCCN criteria or considering familial history or early-onset cases may exclude a substantial number of patients who could potentially benefit from PARP inhibitor treatment. The hormone receptor-positive subgroup is considerable and noteworthy. Retrospective data suggests varied responses to CDK4/6 inhibitors in these patients, prospective studies could explore potential treatment combinations, including PARP inhibitors. In the metastatic context of BRCA1 mutations, the focus has predominantly been on patients undergoing chemotherapy. The potential advantages of incorporating PARP inhibitors in such cases remain unexplored due to limited available data. Furthermore, co-mutations alongside BRCA require ongoing exploration and refinement in clinical approaches.

When endocrine therapy loses its efficacy, the choice narrows to either chemotherapy or ADCs. ADCs essentially function as a form of chemotherapy and the bystander effect may not be the sole explanation for their effectiveness. These drugs exhibit the toxicity associated with chemotherapy while surpassing its efficacy. The experts suggest a novel perspective on future treatment strategies, proposing the early integration of ADCs in the therapeutic continuum. Unlike the conventional progression from a cyclin inhibitor, which leads to a heterogeneous cell population with resistant cells, initiating treatment with ADCs followed by endocrine therapy aims to target resistant cells early. This approach eliminates the need for maintenance endocrine treatment and holds the potential to extend PFS and potentially OS throughout treatment.

This advocates for a transformative shift in the treatment paradigm and it is imperative to explore unconventional approaches and deviate from guideline recommendations, advocating for the continuation of endocrine manipulation until disease refractoriness occurs. By proactively targeting resistant cells earlier in the treatment trajectory, the duration of disease control with endocrine therapy could be extended. In this context, introducing ADCs, known for their superior efficacy compared to chemotherapy and demonstrated survival extension, has the potential to revolutionize the natural course of the disease.

A key point of the discussion pertains to illustrating the patient’s journey. The PFS extends through the use of cyclin inhibitors in the first line. The critical inquiry arises when patients progress, to identify what treatment regimen was used, in which sequence and evaluate consequences to yield significant insights into patient survival. Integrating this understanding is essential in tailoring the design of future clinical trials to align with these critical considerations.

Reference:

Barrios C, Treatment Post-CDK 4/6 Inhibitors. SABCS 2023, #ED04