As reported in The Lancet Oncology by François-Clément Bidard, MD, and colleagues, the French phase III PADA-1 trial has shown that switching to fulvestrant/palbociclib vs continuing first-line aromatase inhibitor (AI)/palbociclib therapy was associated with improved progression-free survival among patients with advanced estrogen receptor–positive, HER2-negative breast cancer with a rising ESR1 mutation level detected in blood (bESR1mut).

François-Clément Bidard, MD

Study Details

The open-label multicenter trial included 1,107 patients enrolled between March 2017 and January 2019. Patients received first-line AI therapy (2.5 mg letrozole, 1 mg anastrozole, or 25 mg exemestane once per day continuously) and palbociclib at 125 mg once per day on days 1 to 21 of 28-day cycles. Those with new or increased bESR1mut in circulating tumor DNA and no synchronous disease progression were randomly assigned to continue with the same therapy or to switch to fulvestrant at 500 mg intramuscularly on day 1 of each 28-day cycle and palbociclib at the same dose.

Patients had bESR1mut status centrally assessed at inclusion, after one treatment cycle, and then once every two cycles.  The co-primary endpoints were investigator-assessed progression-free survival from random assignment and grade ≥ 3 hematologic adverse events in all patients.

Progression-Free Survival

Among the 1,017 patients, 279 (27%) developed rising bESR1mut; 172 (17%) developed rising bESR1mut without synchronous disease progression and were randomly assigned to fulvestrant/palbociclib (n = 88) or to maintained AI/palbociclib (n = 84). Randomly assigned patients had a median follow-up of 35.3 months from study inclusion and 26.0 months from random assignment. Median progression-free survival from random assignment was 11.9 months (95% confidence interval [CI] = 9.1–13.6 months) in the fulvestrant/palbociclib group vs 5.7 months (95% CI = 3.9–7.5 months) in the AI/palbociclib group (stratified hazard ratio = 0.61, 95% CI = 0.43–0.86, P = .0040).

Among 69 patients allocated to the AI/palbociclib group with subsequent disease progression, 47 crossed over to receive fulvestrant/palbociclib as second-line therapy; at a median follow-up of 14.7 months, median progression-free survival among these patients was 3.5 months (95% CI = 2.7–5.1 months).

Severe Hematologic Adverse Events

Among all 1,017 patients, the most common grade ≥ 3 hematologic adverse events were neutropenia (70.3%), lymphopenia (6.5%), and thrombocytopenia (2.0%). The most common after random assignment of the 172 patients were neutropenia (44.3% in fulvestrant/palbociclib group vs 41.7% in AI/palbociclib group) and lymphopenia (4.5% vs 3.6%). Serious adverse events occurred in three randomly assigned patients, including grade 4 neutropenia in one patient (1.1%) in the fulvestrant/palbociclib group, and grade 4 neutropenia in one patient (1.2%) and grade 3 fatigue in one patient (1.2%) in the AI/palbociclib group. One death prior to random assignment (due to pulmonary embolism) was considered related to treatment.

The investigators concluded, “PADA-1 is the first prospective randomized trial showing that the early therapeutic targeting of bESR1mut results in significant clinical benefit. Additionally, the original design explored in PADA-1 might help with tackling acquired resistance with new drugs in future trials.”

Dr. Bidard, of the Institut Curie, Université Versailles Saint-Quentin, Université Paris-Saclay, Paris, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Pfizer. For full disclosures of the study authors, visit thelancet.com.