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.

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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.

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Sequential induction chemotherapy is feasible and active in patients with locally advanced head and neck cancers and may further include recent compounds such as taxanes.