Abstract GS3-05: Fulvestrant-palbociclib vs continuing aromatase inhibitor-palbociclib upon detection of circulating ESR1 mutation in HR+ HER2- metastatic breast cancer patients: Results of PADA-1, a UCBG-GINECO randomized phase 3 trial

Abstract Background: ESR1 mutations are known drivers of resistance to first line aromatase inhibitors (AI)-based therapy in hormone receptor-positive (HR+) HER2- metastatic breast cancer (mBC) patients (pts), but their clinical actionability remains unknown. The randomized phase 3 PADA-1 trial aimed at evaluating the clinical benefit associated with a switch to fulvestrant-palbociclib upon the detection of a rising ESR1 mutation in blood (bESR1mut) in HR+ HER2- mBC pts treated by first line AI-palbociclib.. Methods: PADA-1 (NCT03079011), a multicenter, randomized, open-label, phase 3 trial, enrolled HR+ HER2- mBC pts with no prior therapy for mBC in the absence of AI-resistance. In the first step, pts were treated with AI-palbociclib as first line therapy and underwent centralized bESR1mut screening every two months. Rising bESR1mut+ pts with no clinical/imaging concomitant disease progression were included in the second step, in which they were randomized between continuing the same therapy (standard arm) or switching to fulvestrant-palbociclib (experimental arm). The third step consisted in an optional crossover to fulvestrant-palbociclib following tumor progression for patients randomized in the standard arm. PADA-1 co-primary endpoints were PFS in the second step, and global safety.. Results: Between 03/2017 and 01/2019, 1,017 pts have been included in the first step. After a median time of 15.6 months in the first step, 172 pts with rising bESR1mut and no synchronous disease progression were randomized to continuing AI-palbociclib (N=84 pts) or to fulvestrant-palbociclib (N=88 pts). Among the 172 randomized pts, N=136 PFS events have been observed in the second step after a median follow-up of 26 months. The median PFS was 5.7 months (95%CI[3.9;7.5]) in the AI-palbociclib arm and 11.9 months (95%CI[9.1;13.6]) in the fulvestrant-palbociclib arm (HR=0.63; 95%CI|0.45-0.88], p=0.007). Among the 70 patients who subsequently developed a disease progression in the AI-palbociclib arm, 47 were included in the optional crossover cohort. With a median follow-up of 14.7 months and 37 events, the median second-PFS observed in the cross-over cohort was 3.5 months (95%CI [2.7-5.1]). Treatment safety and validation of the ESR1mut assay are reported separately (poster session #1). Conclusion: PADA-1 reached its primary objective. This first-of-its-kind liquid biopsy-based trial demonstrates that targeting bESR1mut-associated resistance through a change in the endocrine partner of palbociclib is feasible and allows a doubling in the subsequent median progression free survival.. Funding: Pfizer Citation Format: François-Clément Bidard, Anne-Claire Hardy-Bessard, Thomas Bachelot, Jean-Yves Pierga, Jean-Luc Canon, Florian Clatot, Fabrice Andre, Thibault De La Motte Rouge, Barbara Pistilli, Florence Dalenc, Nadine Dohollou, Olivier Arsene, Thierry Petit, Cécilia Riedl, François Morvan, Adina Marti, Emma Lachaier, Mihaela Achille, Michel Gozy, Anne Escande, Dominique Mille, Fanny Trouboul, Laurent Arnould, Ivan Bieche, Anne Pradines, Jerome Lemonnier, Frederique Berger, Suzette Delaloge. Fulvestrant-palbociclib vs continuing aromatase inhibitor-palbociclib upon detection of circulating ESR1 mutation in HR+ HER2- metastatic breast cancer patients: Results of PADA-1, a UCBG-GINECO randomized phase 3 trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS3-05.