PADA-1 Trial: ctDNA Monitoring for Acquired ESR1 Mutations in Advanced Breast Cancer

This is a synopsis of an Insights series featuring Kevin Kalinsky, MD, MS, of Winship Cancer Institute of Emory University, and Erica L. Mayer, MD, MPH, of Dana-Farber Cancer Institute.

Dr Erica Mayer noted that estrogen receptor [ER] mutations are uncommon at hormone receptor-positive [HR+] metastatic breast cancer diagnosis but emerge in about 40% of patients after 6 months of aromatase inhibitor plus CDK4/6 inhibitor therapy. This prompted discussion of the PADA-1 trial evaluating early intervention at detection of endocrine resistance mutations.

Dr Kevin Kalinsky outlined the PADA-1 study design in which patients received an aromatase inhibitor plus palbociclib as initial metastatic treatment. Circulating tumor DNA [ctDNA] was monitored for evolving ESR1 mutations. Upon ESR1 detection without radiographic progression, patients were randomized to continue aromatase inhibitor plus palbociclib or switch to fulvestrant plus palbociclib. Crossover was allowed at progression. The co-primary endpoints were progression-free survival from randomization (PFS1) and from subsequent therapy after progression (PFS2).

Switching endocrine therapy early upon ESR1 emergence improved PFS1. Overall, the switching strategy increased duration of clinical benefit across treatment lines. However, Dr Mayer noted PADA-1 enrollment was small without survival data. Larger validation is needed before changing practice based on early ctDNA changes, despite the provocative signal.

This led to discussion of the ongoing phase III SERENA-6 trial, influenced by the PADA-1 paradigm. ER+ metastatic breast cancer patients on stable first-line aromatase inhibitor plus CDK4/6 inhibitor for ≥6 months enter a screening phase with liquid biopsy monitoring for ESR1 mutations. ESR1 detection triggers randomization to continue current therapy or switch endocrine therapy to the oral selective ER degrader [SERD] camizestrant, assessing impact on progression-free survival.

Dr Mayer shared that SERENA-6’s clinical and genomic screening approach resonates with patients. Beyond evaluating specific interventions, these innovative trials may transform monitoring and decision algorithms in HR+ disease. Key open questions persist around optimal duration of therapy lines guided by molecular changes versus standard radiographic progression. Studies must balance maximizing benefit within lines while preserving options for later. Drs Kalinsky and Mayer believe engaging patients in research is imperative to define new paradigms in HR+ metastatic breast cancer care.

*Video synopsis is AI-generated and reviewed by OncLive editorial staff.