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Next-Generation Oral SERD Camizestrant vs Fulvestrant in Postmenopausal ER+/HER2− Advanced Breast Cancer
TAKE-HOME MESSAGE
- SERENA-2 was a randomised phase II trial that investigated the outcomes of postmenopausal women with ER+/HER2− metastatic breast cancer with recurrence or progression on endocrine therapy. Patients were randomised to receive the oral selective oestrogen receptor degrader camizestrant at varying doses or fulvestrant. The median progression-free survival duration was approximately 7.0 to 8.0 months at varying doses of camizestrant and 3.7 months with fulvestrant. Mild visual effects and sinus bradycardia were the treatment-emergent adverse events related to camizestrant.
- Camizestrant may be safe and effective for patients with endocrine-resistant ER+/HER2− metastatic breast cancer. The 75-mg dose of camizestrant was selected to move forward as the optimal dose for future clinical trials.
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
Resistance to endocrine therapies in hormone receptor-positive breast cancer is challenging. We aimed to assess the next-generation oral selective oestrogen receptor degrader (SERD) and complete oestrogen receptor antagonist, camizestrant, versus the first-approved SERD, fulvestrant, in post-menopausal women with oestrogen receptor-positive, HER2-negative, advanced breast cancer.
METHODS
SERENA-2 is an open-label, randomised, phase 2 trial that is being conducted at 74 study centres across Asia, Europe, the Middle East, and North America. Female patients aged 18 years or older who were post-menopausal with histologically or cytologically confirmed metastastic or locoregional oestrogen receptor-positive, HER2-negative breast cancer, an Eastern Cooperative Oncology Group or WHO performance status of 0 or 1, and disease recurrence or progression on at least one line of endocrine therapy, and no more than one previous endocrine therapy in the advanced setting. Patients were initially randomly assigned (1:1:1:1) to receive oral camizestrant once daily at 75 mg, 150 mg, or 300 mg (until the 300 mg group was closed), or fulvestrant intramuscularly at 500 mg (per label). Randomisation was managed through an interactive web-based system and stratified by previous treatment with CDK4/6 inhibitors and presence of liver and/or lung metastases. The primary objective was to determine clinical efficacy of camizestrant versus fulvestrant at each dose level using the primary endpoint of investigator-assessed progression-free survival, per Response Evaluation Criteria in Solid Tumours (version 1.1), assessed by intention to treat in all randomly assigned patients (full analysis set). No formal statistical comparison for the efficacy analysis of the camizestrant 300 mg dose versus fulvestrant was to be performed. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04214288, and is ongoing.
FINDINGS
Between May 11, 2020, and Aug 10, 2021, 240 patients were randomly assigned to receive camizestrant 75 mg (n=74), 150 mg (n=73), 300 mg (n=20), or fulvestrant (n=73), and were included in the full analysis set. All patients received at least one dose of study drug. Median follow-up was 16·6 months (IQR 12·9-19·4) for the camizestrant 75 mg group, 16·3 months (12·9-18·3) for the camizestrant 150 mg group, and 14·7 months (12·7-20·1) for the fulvestrant 500 mg group. Median progression-free survival was 7·2 months (90% CI 3·7-10·9) with camizestrant 75 mg, 7·7 months (5·5-12·9) with camizestrant 150 mg, and 3·7 months (2·0-6·0) with fulvestrant. The hazard ratio for camizestrant 75 mg versus fulvestrant was 0·59 (90% CI 0·42-0·82; p=0·017), and the hazard ratio for camizestrant 150 mg versus fulvestrant was 0·64 (0·46-0·89; p=0·0090). Treatment-related adverse events occurred in 39 (53%) of 74 patients in the camizestrant 75 mg group, 49 (67%) of 73 patients in the camizestrant 150 mg group, 14 (70%) of 20 patients in the camizestrant 300 mg group, and 13 (18%) of 73 patients in the fulvestrant group. No single grade 3 or worse treatment-emergent adverse event occurred in more than two (3%) patients in any group. Serious treatment-emergent adverse events occurred in six (8%) patients in the camizestrant 75 mg group, seven (10%) patients in the camizestrant 150 mg group, two (10%) patients in the camizestrant 300 mg group, and four (5%) patients in the fulvestrant group. No treatment-related deaths occurred.
INTERPRETATION
Camizestrant at 75 and 150 mg showed a significant benefit in progression-free survival versus fulvestrant. These results support further development of camizestrant for the treatment of oestrogen receptor-positive, HER2-negative breast cancer.
FUNDING
AstraZeneca.
Additional Info
Disclosure statements are available on the authors' profiles:
Camizestrant, a next-generation oral SERD, versus fulvestrant in post-menopausal women with oestrogen receptor-positive, HER2-negative advanced breast cancer (SERENA-2): a multi-dose, open-label, randomised, phase 2 trial
Lancet Oncol 2024 Nov 01;25(11)1424-1439, M Oliveira, D Pominchuk, Z Nowecki, E Hamilton, Y Kulyaba, T Andabekov, Y Hotko, T Melkadze, G Nemsadze, P Neven, V Vladimirov, C Zamagni, H Denys, F Forget, Z Horvath, A Nesterova, M Ajimi, B Kirova, T Klinowska, JPO Lindemann, D Lissa, A Mathewson, CJ Morrow, Z Traugottova, R van Zyl, E ArkaniaFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Advances in endocrine therapy for HR+/HER2− metastatic breast cancer have lagged behind the development of targeted combination drugs such as CDK4/6 inhibitors (CDK4/6is) and PIK3CA inhibitors. Until recently, fulvestrant was the only selective oestrogen receptor degrader (SERD) available after clinical resistance to an aromatase inhibitor was demonstrated, and its efficacy after combination therapy in the first-line setting has been relatively poor. Elacestrant was the first oral SERD approved in 2023, and several others are in active development. The SERENA-2 trial tested the oral SERD camizestrant head-to-head against fulvestrant in patients who had progressed on first-line endocrine therapy with or without a CDK4/6i. Two different doses of camizestrant — 75 mg and 150 mg — were studied. This randomised phase II trial showed the superiority of camizestrant at both dose levels of 75 mg and 150 mg, with progression-free survival durations of 7.2 months (HR, 0.59; 90% CI, 0.42–0.82; P = .017) and 7.7 months (HR, 0.64; 90% CI, 0.46–0.89; P = .0090), respectively, compared with 3.7 months for fulvestrant.
Importantly, patients were tested for ESR1 mutations at the start of the trial and sequentially during the trial. Camizestrant markedly outperformed fulvestrant in this subgroup, representing approximately one-third of the total population. Camizestrant also worked well in patients with prior exposure to CDK4/6is and in those with liver or lung metastases. It was relatively safe, with only 12% of patients experiencing grade 3 or worse toxicities and few requiring dose reductions or interruptions. Specific drug-related toxicities included photopsia (the perception of flashing lights) and asymptomatic bradycardia. The 75-mg dose was selected as the phase III dose to carry forward owing to its comparable efficacy and less toxicity compared with the 150-mg dose. The ongoing phase III trials of camizestrant are eagerly awaited and could establish this agent as another advancement in the treatment of this large subgroup of patients with metastatic breast cancer.