KEY TAKEAWAYS
- PADA-1 is a phase III trial evaluating the efficacy of palbociclib in combination with endocrine therapy in metastatic breast cancer patients.
- Primary endpoints of the trial include grade ≥3 hematological toxicities and progression-free survival in randomized patients.
- The trial will screen patients for emerging or rising ESR1 mutations in ctDNA to trigger an early change from AI plus palbociclib to fulvestrant plus palbociclib treatment.
- Patients with rising ESR1 mutations without tumor progression will be randomized between Arm A and Arm B.
- The trial aims to assess global safety while proving the clinical efficacy of periodic monitoring for ESR1 mutations.
- The trial results will be disseminated in academic conference presentations and international peer-reviewed journals.
The employment of a CDK4/6 inhibitor in conjunction with an aromatase inhibitor (AI) has recently emerged as the preferred method for AI-sensitive primary therapy of advanced breast cancer that is estrogen receptor-positive (ER+) and HER2-negative (HER2-). However, it is noteworthy that a significant proportion of patients receiving this combination therapy will eventually experience disease progression and necessitate additional therapeutic interventions. Numerous studies have demonstrated that the emergence of an ESR1 gene mutation results in resistance to aromatase inhibitors in the advanced stage. The detection of ESR1 mutations in ctDNA can be accomplished through the utilization of a digital PCR assay. The objective of this research is to demonstrate the clinical effectiveness of intermittent surveillance for the emergence or escalation of ESR1 mutations in ctDNA, in order to prompt a timely transition from AI plus palbociclib to fulvestrant plus palbociclib therapy, while concurrently evaluating overall safety.
The PADA-1 study is a phase III clinical trial that is randomized, open-label, and multicentric in nature. The trial is being conducted on patients who are receiving AI and palbociclib as their initial treatment for metastatic ER+HER2- breast cancer. A cohort of 1000 patients will be enrolled and administered palbociclib in conjunction with an aromatase inhibitor for treatment. Regular screening for circulating blood ESR1 mutation detection will be conducted on patients. Up to a total of 200 patients who exhibit a detected increase in circulating ESR1 mutation without any progression of the tumor will be subjected to randomization in a 1:1 ratio. The randomization will be conducted between two arms, namely Arm A, which involves no modification of therapy, and Arm B, which involves the administration of palbociclib in combination with fulvestrant, a selective ER down-regulator. Patients randomized in arm A will be offered an optional crossover upon tumor progression. The coprimary endpoints consist of (1) the occurrence of hematological toxicities of Grade ≥3 and their correlation with baseline characteristics and (2) the progression-free survival in patients who were randomly assigned. The research received approval from the French Medicines Agency (ANSM) and an ethics committee (ref 01/17_1 CPP Ouest-IV Nantes) in January 2017. The trial findings shall be disseminated through academic conference presentations and international peer-reviewed publications.
Source:https://pubmed.ncbi.nlm.nih.gov/35241469/
Clinical trial: https://clinicaltrials.gov/ct2/show/NCT03079011
Berger F, Marce M, Delaloge S, Hardy-Bessard AC, Bachelot T, Bièche I, Pradines A, De La Motte Rouge T, Canon JL, André F, Arnould L, Clatot F, Lemonnier J, Marques S, Bidard FC; PADA-1 investigators. Randomized, open-label, multicentric phase III trial to evaluate the safety and efficacy of palbociclib in combination with endocrine therapy, guided by ESR1 mutation monitoring in estrogen receptor-positive, HER2-negative metastatic breast cancer patients: study design of PADA-1. BMJ Open. 2022 Mar 3;12(3):e055821. doi: 10.1136/bmjopen-2021-055821. PMID: 35241469; PMCID: PMC8896060.
