Advancements in Targeted Therapies for CDK4/6 Inhibitor-Resistant HR+ Breast Cancer

In a significant development for the treatment of hormone receptor-positive (HR+) metastatic breast cancer, recent discussions led by Dr. Kevin Kalinsky, MD, MS, FASCO, highlight the critical importance of optimizing endocrine-based therapies, particularly in patients resistant to CDK4/6 inhibitors. This examination comes in the wake of new promising investigational regimens, suggesting a shift in the treatment paradigm for this challenging patient population.

Dr. Kalinsky, a distinguished professor and director of the Division of Medical Oncology at Emory University School of Medicine, emphasizes that molecular testing plays a pivotal role in guiding treatment decisions for patients who exhibit resistance to standard therapies. "For as long as possible, we want patients to receive therapy that is well tolerated and does not require extensive time in infusion centers," he stated during an interview with OncLive®.

The discussion is framed against the backdrop of findings from the recent ASCO Annual Meeting, where the final overall survival analysis of the phase 3 INAVO120 trial was presented. This trial demonstrated that first-line treatment with inavolisib (Itovebi) in combination with palbociclib (Ibrance) and fulvestrant (Faslodex) significantly improved overall survival compared to placebo in patients with PIK3CA-mutated, HR+, HER2-negative, endocrine-resistant advanced breast cancer (HR, 0.67; 95% CI, 0.48-0.94; P = .0190).

Moreover, the phase 3 postMONARCH trial indicates that patients who experience disease progression after treatment with a prior CDK4/6 inhibitor may benefit from a subsequent treatment with another CDK4/6 inhibitor, specifically abemaciclib in combination with fulvestrant, which showed a notable improvement in progression-free survival (PFS) compared to placebo (HR, 0.73; 95% CI, 0.57-0.95; P = .017).

Despite these advancements, Dr. Kalinsky acknowledges the challenges that remain in the treatment landscape. Resistance to CDK4/6 inhibitors can complicate therapy sequencing and patient adherence. He notes the significance of testing for molecular alterations, such as ESR1, PTEN, AKT, and PIK3CA mutations, particularly at the point of disease progression, to inform subsequent treatment strategies.

The discussion also underscores the importance of considering various therapeutic options based on patient characteristics and prior treatment history. For example, patients with low-volume, bone-only disease may benefit from elacestrant, while those with PI3K mutations could be candidates for fulvestrant plus capivasertib.

Looking ahead, Dr. Kalinsky expresses hope for the approval of several novel agents, including camizestrant and vepdegestrant, which are currently not available in clinical practice but show promise based on trial data. He highlights the importance of ensuring that patients tolerate prescribed therapies, as poor adherence can diminish treatment efficacy.

In conclusion, the ongoing research and clinical trials present a beacon of hope for patients battling HR+ breast cancer resistant to CDK4/6 inhibitors. As new therapies continue to emerge, the focus remains on providing personalized, effective treatment options that enhance patient quality of life while delaying disease progression. The necessity for ongoing research and the refinement of treatment strategies is paramount as the medical community strives to address the unmet needs of this patient population.