Clinical activity of camizestrant, a next-generation SERD, versus fulvestrant in patients with a detectable ESR1 mutation: Exploratory analysis of the SERENA-2 phase 2 trial.

Abstract

1066 Background: Camizestrant, a next-generation oral selective estrogen receptor antagonist and degrader (ngSERD), was compared at two dose levels to fulvestrant 500 mg (F) in post-menopausal women with advanced ER+, HER2˗ breast cancer with disease recurrence or progression after ≤1 endocrine therapy in the advanced setting in the Phase 2 randomized SERENA-2 study (NCT04214288). Camizestrant demonstrated statistically significant and clinically meaningful benefit vs F in progression-free survival (PFS) in the overall study population (Oliveira M et al. SABCS 2022 Annual Meeting. Abstract GS3-02.). Methods: Baseline circulating tumour DNA was collected at screening and/or Cycle 1 Day 1 and analysed by next-generation sequencing. A post hoc exploratory analysis compared investigator assessed PFS with camizestrant (data from 75 and 150 mg combined) vs F in patients with detectable baseline ESR1 (the gene that encodes ERα) hotspot mutations ( ESR1m). Patients were divided into subgroups based on whether 1 or >1 ESR1m variants were detected, the specific ESR1m, and whether mutations were detected in BRCA1/2 or the MAPK pathway. The most prevalent mutations are presented. A Cox proportional hazards model was used to compare PFS. Results: 48/147 (32.7%) patients treated with camizestrant and 35/73 (47.9%) treated with F had a detectable ESR1m in at least 1 baseline sample. ESR1m were detected in 6/9 (67%) patients with a BRCA1/2 mutation and 5/26 (19%) with a MAPK pathway alteration; however, the numbers were too small to analyse efficacy in these subgroups. Conclusions: Camizestrant showed improved outcome vs F in patients with a detectable ESR1m at baseline and in the subgroups tested. The greatest median PFS improvement was seen in patients where a single ESR1m variant was detected, suggesting that early intervention upon detection of an ESR1m may provide the maximum patient benefit for camizestrant, a hypothesis that is being tested in the SERENA-6 clinical trial (NCT04964934). Clinical trial information: NCT04214288 . [Table: see text]

Reply to Y. Yoshitomi et al

“…More recent trials including AMEERA-3, EMERALD, VERONICA acelERA, and SERENA-2 recruited patients who had previously been treated with CDK4/6 inhibitors, a reflection of the update in the standard of care. 2,5,8-10 In the EMERALD, VERONICA, acelERA, and SERENA-2 studies, the median PFS for the control arm (endocrine monotherapy) was 1.9, 1.9, 5.4, and 3.7 months, respectively, in line with what was observed in AMEERA-3. We believe that the previous exposure to a CDK4/6 inhibitor is a key factor that led to shorter PFS.…”

The Treatment Landscape of Elderly Patients with Hormone Receptor-Positive Her2 Negative Advanced Breast Cancer: Current Perspectives and Future Directions

“…In recent years, the treatment landscape of HR+/Her2-negative mBC has completely changed, thanks to the introduction of particularly active targeted drugs, from CDK4/6 inhibitors [ 26 , 27 , 28 , 29 , 30 , 31 , 32 ], mTOR inhibitors [ 33 ] and PARP inhibitors [ 34 , 35 ], to new oral SERDs [ 36 , 37 , 38 ] and PI3K inhibitors [ 39 , 40 , 41 , 42 ], which have expanded the treatment armamentarium and improved survival outcomes for this patient population. Moreover, other new active drugs are increasingly appearing in the setting of HR+ mBC, such as antibody–drug conjugates (ADC) [ 43 , 44 ], which have recently demonstrated their clinical efficacy regardless of the expression of HRs, PROteolysis Targeting Chimeras (PROTACs) [ 45 ], selective estrogen receptor covalent antagonists (SERCA) [ 46 ] and complete estrogen receptor antagonists (CERAN) [ 25 ].…”

Liquid biopsy to tailor the treatment of advanced hormone receptor-positive breast cancer in the era of novel endocrine agents and CDK4/6-inhibitors

“…Interestingly, patients in this study with rising ESR1 mutations in ctDNA experienced improved PFS when switched to fulvestrant and palbociclib, as opposed to continuing AI as ET backbone ( 18 ). New oral SERDs like elacestrant or camizestrant also proved to be particularly effective, and superior to fulvestrant, in ESR1 -mutant HR + /HER2 − ABC, as detected in ctDNA ( 7 , 19 ). These and other novel agents are currently under investigation in combination with CDK4/6-inhibitors ( 7 ).…”