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 S 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.