Switch to Fulvestrant and Palbociclib vs No Switch in Advanced Breast Cancer With Rising ESR1 Mutations During Aromatase Inhibitor and Palbociclib Therapy
abstract
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Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
In advanced oestrogen receptor-positive, HER2-negative breast cancer, acquired resistance to aromatase inhibitors frequently stems from ESR1-mutated subclones, which might be sensitive to fulvestrant. The PADA-1 trial aimed to show the efficacy of an early change in therapy on the basis of a rising ESR1 mutation in blood (bESR1mut), while assessing the global safety of combination fulvestrant and palbociclib.
METHODS
We did a randomised, open-label, phase 3 trial in 83 hospitals in France. Women aged at least 18 years with oestrogen receptor-positive, HER2-negative advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited and monitored for rising bESR1mut during first-line aromatase inhibitor (2·5 mg letrozole, 1 mg anastrozole, or 25 mg exemestane, orally once per day, taken continuously) and palbociclib (125 mg orally once per day on days 1-21 of a 28-day cycle) therapy. Patients with newly present or increased bESR1mut in circulating tumour DNA and no synchronous disease progression were randomly assigned (1:1) to continue with the same therapy or to switch to fulvestrant (500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1) and palbociclib (dosing unchanged). The randomisation sequence was generated within an interactive web response system using a minimisation method (with an 80% random factor); patients were stratified according to visceral involvement (present or absent) and the time from inclusion to bESR1mut detection (<12 months or ≥12 months). The co-primary endpoints were investigator-assessed progression-free survival from random assignment, analysed in the intention-to-treat population (ie, all randomly assigned patients), and grade 3 or worse haematological adverse events in all patients. The trial is registered with Clinicaltrials.gov (NCT03079011), and is now complete.
FINDINGS
From March 22, 2017, to Jan 31, 2019, 1017 patients were included, of whom 279 (27%) developed a rising bESR1mut and 172 (17%) were randomly assigned to treatment: 88 to switching to fulvestrant and palbociclib and 84 patients to continuing aromatase inhibitor and palbociclib. At database lock on July 31, 2021, randomly assigned patients had a median follow-up of 35·3 months (IQR 29·2-41·4) from inclusion and 26·0 months (13·8-34·3) from random assignment. Median progression-free survival from random assignment was 11·9 months (95% CI 9·1-13·6) in the fulvestrant and palbociclib group versus 5·7 months (3·9-7·5) in the aromatase inhibitor and palbociclib group (stratified HR 0·61, 0·43-0·86; p=0·0040). The most frequent grade 3 or worse haematological adverse events were neutropenia (715 [70·3%] of 1017 patients), lymphopenia (66 [6·5%]), and thrombocytopenia (20 [2·0%]). The most common grade 3 or worse adverse events in step 2 were neutropenia (35 [41·7%] of 84 patients in the aromatase inhibitor and palbociclib group vs 39 [44·3%] of 88 patients in the fulvestrant and palbociclib group) and lymphopenia (three [3·6%] vs four [4·5%]). 31 (3·1%) patients had grade 3 or worse serious adverse events related to treatment in the overall population. Three (1·7%) of 172 patients randomly assigned had one serious adverse event in step 2: one (1·2%) grade 4 neutropenia and one (1·2%) grade 3 fatigue among 84 patients in the aromatase inhibitor and palbociclib group, and one (1·1%) grade 4 neutropenia among 88 patients in the fulvestrant and palbociclib group. One death by pulmonary embolism in step 1 was declared as being treatment related.
INTERPRETATION
PADA-1 is the first prospective randomised 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.
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Additional Info
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Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial
Lancet Oncol 2022 Sep 29;[EPub Ahead of Print], FC Bidard, AC Hardy-Bessard, F Dalenc, T Bachelot, JY Pierga, T de la Motte Rouge, R Sabatier, C Dubot, JS Frenel, JM Ferrero, S Ladoire, C Levy, MA Mouret-Reynier, A Lortholary, J Grenier, C Chakiba, L Stefani, JE Plaza, F Clatot, L Teixeira, V D'Hondt, H Vegas, O Derbel, C Garnier-Tixidre, JL Canon, B Pistilli, F André, L Arnould, A Pradines, I Bièche, C Callens, J Lemonnier, F Berger, S DelalogeFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The PADA-1 trial is the first study of patients with metastatic breast cancer that explored whether outcomes can be improved with the strategy of switching therapy based on genomic findings prior to clinical progression. In this trial, patients with HR+/HER2– metastatic breast cancer who were responding well to an aromatase inhibitor (AI) plus palbociclib therapy were monitored every 2 months using the circulating tumor DNA analysis to detect the emergence of activating ESR1 mutations, which can confer resistance to AIs. Upon the detection of increasing mutations in the blood without radiographic progression, patients were randomized to continue the AI plus palbociclib therapy versus switching treatment to fulvestrant with the continuation of palbociclib. There was an optional crossover to fulvestrant–palbociclib therapy following tumor progression for patients randomized to stay on AI-palbociclib therapy. The median duration of progression-free survival (PFS) was 5.7 months in the AI-palbociclib arm compared with 11.9 months in the fulvestrant–palbociclib arm (HR, 0.60; 95% CI, 0.42–0.85; P = .004). The median duration of the second PFS observed in the crossover cohort was 3.5 months (95% CI, 2.7–5.1). The trial was a great effort that evaluated a treatment approach that is commonly used in many other cancer types, and the findings were thought-provoking. However, prior to the routine use of this approach, there are remaining questions, including whether there are more appropriate endpoints than PFS, the impact on overall survival, and whether there are other biomarkers that could be used to detect resistance to therapy. Finally, we await further ongoing studies that will help clarify whether there is value in the continuation of CDK4/6 inhibitors beyond progression.