Prognostic impact of ESR1 mutations in ER+ HER2- MBC patients prior treated with first line AI and palbociclib: An exploratory analysis of the PADA-1 trial.

Abstract

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Background: The question of which is the best endocrine partner to CDK4/6 inhibitors in first line for ER+ HER2- metastatic breast cancer (MBC) remains open. ESR1 mutations might be of paramount importance, as they confer resistance to AI but not to SERD. In pts treated with first line palbociclib-AI combination (PADA-1 trial, NCT03079011), we investigated ESR1mut detection rate at inclusion, prior to any therapy, and their prognostic impact. Methods: The PADA-1 phase 3 trial (NCT03079011, UCBG-GINECO) evaluates the utility of monitoring the onset of ESR1mut in cell-free DNA (with a ddPCR assay [Jeannot et al, Oncogene 2020]) of pts receiving AI-palbociclib in first line. Included pts had no prior therapy for MBC and no overt resistance to AI. Results: N = 1017 ER+ HER2- MBC pts were included in 22 months from 04/2017 and had their cfDNA tested for ESR1mut at inclusion and during therapy. N = 33/1017 pts had a detectable circulating ESR1mut at inclusion (3.2%, 95%CI [2.2;4.5]), ESR1mut positivity being associated with a prior exposure to AI in the adjuvant setting (p < 0.01). N = 1 pt died after 1 month on treatment. In N = 25/32 evaluable pts (78%), ESR1mut became undetectable in cfDNA (AF < 0.1%) within the first 5 months on treatment, with a median time to ESR1mut ‘clearance’ of 34 days. Among these 25 pts, 14 pts (56%) had ESR1mut detected again during therapy; 2 pts (8%) experienced a progression with no ESR1mut detected; the remaining 9 patients (36%) were still both ESR1mut -free and progression-free at time of analysis. With a median FU time of 12.4 months (range: 0-25.3m) under AI-palbociclib, the 33 ESR1mut-positive pts had a shorter PFS (median: 17.5mo, 95%CI[10.5-NR]) than the 984 ESR1mut-negative pts (median not reached), with an estimated HR = 2.8 [1.6;5.0]. Updated data will be presented at the meeting. Conclusions: ESR1mut are rarely detected in the cfDNA of ER+ HER2- MBC patients with no overt resistance to AI. The quick ‘clearance’ of ESR1mut under treatment and the observed 17.5 months-long median PFS both suggest that the AI-palbociclib combination retain a clinical activity in this population. ESR1mut-positivity prior was however associated with a significantly shorter PFS, suggesting that ESR1mut positivity at baseline could accelerate the onset of resistance to AI-palbociclib. These findings may put into perspective the incoming results of the PARSIFAL trial. Clinical trial information: NCT03079011 .