Abstract P1-18-16: First line aromatase inhibitor (AI) + palbociclib with randomized switch to fulvestrant + palbociclib upon detection of circulating ESR1 mutation in HR+ HER2- metastatic breast cancer patients: Global safety results of PADA-1, a UCBG-GINECO phase III trial
Authors: Delaloge Suzette , Hardy-Bessard Anne-Claire , Bachelot Thomas , Pierga Jean-Yves , Canon Jean-Luc , Clatot Florian , André Fabrice , Rouge Thibault De La Motte , Pistilli Barbara , Dalenc Florence , Dohollou Nadine , Arsene Olivier , Petit Thierry , Riedl Cecilia , Morvan François , Marti Adina , Lachaier Emma , Achille Mihaela , Gozy Michel , Escande Anne , Mille Dominique , Trouboul Fanny , Marques Sandrine , Lemonnier Jerome , Berger Frederique , Bidard François-Clément 
Published: March 2022

Abstract
Background: Aromatase inhibitors (AI) in combination with a CDK 4/6 inhibitor have been established as the standard first line treatment of non AI-resistant hormone receptor-positive (HR+) HER2- metastatic breast cancer (mBC) patients (pts). ESR1 mutations are known drivers of resistance to AIs in the metastatic setting but their actionability remains unknown. The phase 3 PADA-1 trial aimed both at refining the global safety of palbociclib combined to any AI as first line treatment of HR+ HER2- mBC pts, and at evaluating the clinical benefit associated with a switch to fulvestrant-palbociclib upon detection of a rising ESR1 mutation in blood (bESR1mut). 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 received a combination of any AI and palbociclib at standard recommended doses and underwent centralized bESR1mut screening every two months. In the second step, bESR1mut+ pts with no clinical/imaging concomitant disease progression were randomized between continuing the same therapy (standard arm) or switching to fulvestrant-palbociclib (experimental arm). The third step consisted in an optional cross-over after tumor progression for patients randomized in the standard arm. PADA-1 co-primary endpoints were global safety of the combination of palbociclib + endocrine therapy in the whole population of patients, throughout the study, with focus on hematological toxicities; and PFS in the second step. We present here the results of the global safety co-primary endpoint. Results: From 3/2017 to 01/2019, 1017 pts were accrued in 83 sites. As per 05/2021, 272 pts were still in step 1, 35 in step 2, and 8 in step 3. The overall follow-up was 33.7 months. 232 pts have deceased. 333 SAEs have been reported, including 21 grade 5, 35 grade 4, 183 grade 3, 53 grade 2, 26 grade 1 and 15 unknown grade. Among the grade 5 cases, 2 have been declared as potentially related to the underlying treatment (Death of unknown cause, pulmonary embolism). No pt died of SARS-CoV2 infection. The main hematological toxicities encountered, as well as selected non-hematological events are described in Table 1. Permanent discontinuation of the treatment due to toxicity occurred in 39 pts/1017 (3.8%). Palbociclib dose decreases occurred in 419 (41.2%) pts. Conclusion: By the number of included patients, PADA-1 is the largest prospective trial with 1st line AI and palbociclib. Data confirm the favorable safety profile of palbociclib when combined to any AI +/- switch to fulvestrant. Hematological toxicity appears limited and is mostly restricted to non-clinically significant neutropenia. Permanent discontinuation was exceptional. Detailed per-step analyses will be presented.
Table 1.Adverse events (% pts)Grade 3, N (%)Grade 4, N (%)Neutropenia628 (61.8%)83 (8.2%)Febrile neutropenia4 (0.4%)0Thrombocytopenia18 (1.8%)3 (0.3%)Anemia24 (2.4%)0Lymphocytopenia58 (5.7%)5 (0.5%)Insterstitial lung disease4 (0.4%)0Liver enzymes increase (AST/ALT)5 (0.5%)0Mucositis10 (1%)0
Citation Format: Suzette Delaloge, Anne-Claire Hardy-Bessard, Thomas Bachelot, Jean-Yves Pierga, Jean-Luc Canon, Florian Clatot, Fabrice André, Thibault De La Motte Rouge, Barbara Pistilli, Florence Dalenc, Nadine Dohollou, Olivier Arsene, Thierry Petit, Cecilia Riedl, François Morvan, Adina Marti, Emma Lachaier, Mihaela Achille, Michel Gozy, Anne Escande, Dominique Mille, Fanny Trouboul, Sandrine Marques, Jerome Lemonnier, Frederique Berger, François-Clément Bidard. First line aromatase inhibitor (AI) + palbociclib with randomized switch to fulvestrant + palbociclib upon detection of circulating ESR1 mutation in HR+ HER2- metastatic breast cancer patients: Global safety results of PADA-1, a UCBG-GINECO phase III 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 P1-18-16.