Abstract OT2-11-05: SERENA-6: A Phase III study to assess the efficacy and safety of AZD9833 (camizestrant) compared with aromatase inhibitors when given in combination with palbociclib or abemaciclib in patients with HR+/HER2- metastatic breast cancer with detectable ESR1m who have not experienced disease progression on first-line therapy
Authors: Bidard François-Clément , Kalinsky Kevin , Cristofanilli Massimo , Bianchini Giampaolo , Chia Stephen KL , Janni Wolfgang , Ma Cynthia X , Mayer Erica L , Park Yeon Hee , Fox Steven , Liu Xiaochun , Walding Andrew , Bartlett Cynthia Huang , Turner Nick C 
Published: March 2022

Abstract
Background: More than two thirds of patients with metastatic breast cancer (mBC) have hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) tumors. Current guidelines recommend combining endocrine therapy (ET), such as an aromatase inhibitor (AI), with an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6i) as first-line (1L) treatment (Cardoso et al. Ann Oncol 2020). However, drug resistance eventually develops, leading to disease progression. Mutations in the estrogen receptor (ER) alpha gene (ESR1m) result in constitutively active, estrogen-independent ER signaling which can reduce AI efficiency (Reinert et al. Front Oncol 2017). Clinically, ESR1m are associated with acquired resistance to AI as well as more aggressive disease features, including development of visceral metastasis (Gerratana et al. Eur J Cancer 2021). At the initial diagnosis of mBC, the frequency of ESR1m is low (approximately 3%) (Bidard et al. Ann Oncol 2019); however, this increases to 17−35% of patients when disease progresses on an AI + CDK4/6i (Bidard et al. Ann Oncol 2019; Goetz et al. J Clin Oncol 2020). Patients with ESR1m tumors have poor outcomes with subsequent lines of therapy. New approaches are needed to maximize time on 1L treatment with ET + CDK4/6i and prevent further clinical and radiological disease progression. AZD9833 (camizestrant) is a highly potent, next-generation oral selective ER degrader (ngSERD) and pure ER antagonist that has demonstrated antitumor activity in a wide range of ER+ breast cancer cell lines and patient-derived xenograft models, including those with wild type ESR1 (ESR1wt) and the most prevalent ESR1m, D538G and Y537S (Scott et al. AACR 2020; Lawsone et al. AACR 2020). The Phase I SERENA-1 study demonstrated that AZD9833 shows encouraging clinical activity as monotherapy or in combination with a CDK4/6i in heavily pre-treated patients with ER+/HER2− advanced breast cancer whose tumors are ESR1wt or ESR1m (Baird et al. SABCS 2020). SERENA-6 will assess the efficacy of switching patients from AI to AZD9833, while continuing CDK4/6i treatment, once ESR1m are detected but before overt disease progression. Study description: SERENA-6 is an ongoing, randomized, multicenter, double-blind, Phase III trial. Patients with HR+/HER2− mBC who have received at least 6 months of 1L AI (letrozole or anastrozole) + CDK4/6i (palbociclib or abemaciclib) and do not have clinical or radiological disease progression will be enrolled into Step 1, the ESR1m detection phase. During this phase, patients will be monitored regularly for the presence of ESR1m via central circulating tumor DNA analysis. Patients with detectable ESR1m and no overt disease progression (by RECIST v1.1 criteria) will be enrolled into Step 2 double-blind 1:1 randomization to either continue AI plus CDK4/6i, plus a placebo for AZD9833, or switch to AZD9833 (75 mg oral once daily), plus the same CDK4/6i plus a placebo for the AI. The primary endpoint will be investigator-assessed progression-free survival (PFS) per RECIST v1.1 criteria. A key secondary endpoint will be time to second progression or death on a subsequent therapy. Other secondary endpoints will include overall survival, chemotherapy-free survival, objective response rate, clinical benefit rate, patient-reported outcomes, and safety. Enrollment began in June 2021 and is expected at approximately 200 sites across 19 countries. Acknowledgments: We thank Julia Mawer, PhD, of Oxford PharmaGenesis, UK, for medical writing assistance, which was funded by AstraZeneca. Funding: The SERENA-6 trial is funded and overseen by AstraZeneca.
Citation Format: François-Clément Bidard, Kevin Kalinsky, Massimo Cristofanilli, Giampaolo Bianchini, Stephen KL Chia, Wolfgang Janni, Cynthia X Ma, Erica L Mayer, Yeon Hee Park, Steven Fox, Xiaochun Liu, Andrew Walding, Cynthia Huang Bartlett, Nick C Turner. SERENA-6: A Phase III study to assess the efficacy and safety of AZD9833 (camizestrant) compared with aromatase inhibitors when given in combination with palbociclib or abemaciclib in patients with HR+/HER2- metastatic breast cancer with detectable ESR1m who have not experienced disease progression on first-line therapy [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 OT2-11-05.