The Power of PADA-1: Palbociclib and Circulating Tumor DNA in Detecting ESR1 Mutations

In advanced breast cancer cases with positive estrogen receptors and negative HER2 receptors, resistance to aromatase inhibitors is often due to the presence of mutated subclones of the ESR1 gene. Fulvestrant may be effective in treating these subclones. The objective of the PADA-1 clinical trial was to demonstrate the effectiveness of an early modification in treatment protocol in response to an increasing presence of ESR1 mutation in the bloodstream (bESR1^mut). Additionally, the study evaluated the overall safety of a combined therapy involving fulvestrant and palbociclib. A phase 3 trial was conducted in 83 hospitals across France, which was randomized and open-label in nature. Female patients who were at least 18 years old, had advanced breast cancer that was positive for estrogen receptor but negative for HER2, and had an Eastern Cooperative Oncology Group performance status of 0-2, were enrolled in the study. They were closely monitored for an increase in bESR1^mut during their first-line treatment with aromatase inhibitors (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). Subjects displaying recently detected or elevated bESR1^mut  in circulating tumor DNA and lacking concurrent disease progression were arbitrarily allocated in a 1:1 ratio to either maintain their current treatment or transition to a regimen consisting of fulvestrant (administered intramuscularly at a dose of 500 mg on the first day of each 28-day cycle and on day 15 of cycle 1) and palbociclib (dosing regimen unchanged). The randomization sequence was produced through an interactive web response system utilizing a minimization technique with an 80% randomization factor. Stratification of patients was based on visceral involvement (present or absent) and the duration from inclusion to bESR1^mut detection (<12 months or ≥12 months). The study evaluated two co-primary endpoints: investigator-assessed progression-free survival from a random assignment in the intention-to-treat population and grade 3 or worse hematological adverse events in all patients.

Between March 22, 2017, and Jan 31, 2019, a total of 1017 patients were enrolled. Among them, 279 (27%) exhibited an increase in bESR1^mut. Out of the total, 172 (17%) were randomly selected for treatment. Of these, 88 patients were subjected to fulvestrant and palbociclib, while 84 patients continued with aromatase inhibitors and palbociclib. At the time of database lock on July 31, 2021, patients who were randomly assigned had a median follow-up duration of 35.3 months (interquartile range [IQR] 29.2-41.4) from the time of inclusion and 26.0 months (IQR 13.8-34.3) from the time of random assignment. The median progression-free survival from the random assignment was 11.9 months (95% CI 9.1-13.6) in the group treated with fulvestrant and palbociclib, compared to 5.7 months (3.9-7.5) in the group treated with aromatase inhibitor and palbociclib. The stratified hazard ratio was 0.61 (0.43-0.86) with a P= 0.0040. The most commonly observed grade 3 or higher hematological adverse events included neutropenia (715 [70·3%] out of 1017 patients), lymphopenia (66 [6·5%]), and thrombocytopenia (20 [2·0%]). The prevalent grade 3 or more severe unfavorable occurrences observed in phase 2 were neutropenia (35 [41.7%] of 84 patients in the aromatase inhibitor and palbociclib group versus 39 [44.3%] of 88 patients in the fulvestrant and palbociclib group) and lymphopenia (three [3.6%] versus four [4.5%]). In the overall population, 31 (3·1%) patients experienced serious adverse events of grade 3 or higher that were related to the treatment. In step 2 of the study, among the 172 patients who were randomly assigned, three individuals (1.7%) experienced a serious adverse event. Specifically, one patient (1.2%) in the aromatase inhibitor and palbociclib group experienced grade 4 neutropenia, while another patient (1.2%) in the same group experienced grade 3 fatigue. In the fulvestrant and palbociclib group, one patient (1.1%) experienced grade 4 neutropenia out of 88 patients. A fatality due to pulmonary embolism during step 1 was deemed to be associated with the treatment. The PADA-1 study is the initial randomized trial that demonstrated the advantageous clinical outcomes of promptly targeting therapeutic interventions towards bESR1^mut. Furthermore, the initial prototype investigated in PADA-1 may aid in addressing the development of acquired resistance to novel medications in upcoming clinical studies.

Source: https://pubmed.ncbi.nlm.nih.gov/36183733/

Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT03079011

Bidard FC, Hardy-Bessard AC, Dalenc F, Bachelot T, Pierga JY, de la Motte Rouge T, Sabatier R, Dubot C, Frenel JS, Ferrero JM, Ladoire S, Levy C, Mouret-Reynier MA, Lortholary A, Grenier J, Chakiba C, Stefani L, Plaza JE, Clatot F, Teixeira L, D’Hondt V, Vegas H, Derbel O, Garnier-Tixidre C, Canon JL, Pistilli B, André F, Arnould L, Pradines A, Bièche I, Callens C, Lemonnier J, Berger F, Delaloge S; PADA-1 investigators. 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 Nov;23(11):1367-1377. doi: 10.1016/S1470-2045(22)00555-1. Epub 2022 Sep 29. PMID: 36183733.