First-line fulvestrant vs. anastrozole in hormone receptor-positive advanced breast cancer: insights from the final FALCON trial results

The management paradigm for hormone receptor-positive (HR⁺) advanced breast cancer has evolved dramatically with improvements in endocrine therapy (ET), notably through aromatase inhibitors (AIs), selective estrogen receptor degraders (SERDs), and more recently, the addition of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors (1). Despite the introduction of novel agents and combinations, the choice of first-line ET remains a pivotal decision point for clinicians. The FALCON trial, a landmark phase III study, provides valuable evidence for optimizing therapy selection, comparing fulvestrant with anastrozole in postmenopausal women naïve to prior ET (2).

FALCON enrolled 462 postmenopausal women with HR⁺, human epidermal growth factor receptor 2-negative (HER2⁻) advanced breast cancer who had not previously received systemic ET in the advanced setting. The randomized, double-blind design compared fulvestrant 500 mg with anastrozole 1 mg as first-line ET. Stratification by visceral and nonvisceral metastases allowed granular analysis of how metastatic site influences therapeutic benefit, a factor increasingly recognized as clinically significant. Tab. 1 summarizes baseline characteristics, confirming balanced demographics (median age 62–64 years), performance status, prior treatments, and distribution of metastatic sites (3).

At the preplanned final analysis (68% events, cutoff July 2022), median follow-up exceeded 3 years per arm. The intention-to-treat cohort revealed no statistically significant difference in median overall survival (OS): 44.8 months for fulvestrant vs. 42.7 months for anastrozole [hazard ratio 0.97, 95% confidence interval (CI): 0.77–1.21]. Subgroup analyses, however, tell a more nuanced story. In patients with nonvisceral disease, fulvestrant showed a trend toward improved OS (65.2 vs. 47.8 months, hazard ratio 0.85, 95% CI: 0.60–1.20), corresponding to a sizable 17.4-month median OS benefit and a 15% reduction in relative risk of death, though not reaching statistical significance. Exploratory analysis in this nonvisceral population found the greatest absolute OS gain with fulvestrant (65.2 months) compared to those with visceral metastases (37.2 months, hazard ratio 0.62, 95% CI: 0.45–0.85). These results are consistent across multiple subgroups and echo findings from the pivotal FIRST, CONFIRM, MONALEESA, and SWOG S0226/MONARCH 2 trials (4-9).

Long-term safety data in FALCON reaffirm prior reports: both therapies exhibited low rates of serious adverse events, treatment discontinuations, and deaths directly linked to study drugs. No new safety signals emerged over 8 years of monitoring. The health-related quality of life (HRQOL) assessments further support the excellent tolerability of both drugs, with no clinically meaningful differences across arms through prolonged therapy (2,3,10).

Real-world treatment following study therapy progressed similarly for both arms: about half of the patients received post-study anticancer therapies, including other ET agents, chemotherapy, and radiotherapy. Use of newer agents such as CDK4/6 inhibitors was infrequent overall (<5% per arm), reflecting trial timing and global access trends. Tab. 3 in the FALCON report provides a comprehensive distribution of these subsequent therapies, showing parallel real-world management across both trial groups (1,11).

Meta-analyses and translational studies have clarified that metastatic site is not a mere reflection of tumor burden, but a proxy for underlying disease biology and endocrine sensitivity. Patients with nonvisceral (bone, skin, breast-only, soft tissue) involvement typically retain higher estrogen receptor (ER) and progesterone receptor (PR) levels, have lower proliferation indices (Ki-67), and fewer pathway mutations driving resistance, correlating with augmented benefit from endocrine monotherapy. Mechanistically, fulvestrant induces near-complete degradation of ER protein, whereas nonsteroidal aromatase inhibitors (NSAIs) suppress estrogen synthesis but leave ER available for possible ligand-independent, phosphorylated ER-driven signaling. Consistent with this concept, Vergote et al. reported that anastrozole retained activity as second-line therapy after fulvestrant, supporting the feasibility of sequential fulvestrant-NSAI use in advanced breast cancer (12).

FALCON reinforces this observation by demonstrating substantially higher median OS for nonvisceral disease with fulvestrant therapy, a finding mirrored in earlier subgroup and post hoc analyses (3).

International consensus from the European Society for Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO), and National Comprehensive Cancer Network (NCCN) similarly recommend initial ET subject to individual patient risk, comorbidities, and metastatic pattern, in endocrine-sensitive, nonvisceral cases, reserving chemotherapy for symptomatic or rapidly progressing disease (6). The landscape of ET continues to shift: while fulvestrant remains a gold-standard SERD for first-line and second-line use, newer oral SERDs such as elacestrant, camizestrant, amcenestrant, giredestrant, and imlunestrant, etc., are changing therapeutic possibilities, with promising data emerging for ET-resistant disease and ESR1-mutant populations (13-15).

Recent advances in CDK4/6 inhibitor therapy have also expanded treatment options. The 2024–2025 literature confirms that CDK4/6 inhibitors combined with fulvestrant remain standard first-line treatment for both premenopausal and postmenopausal women with HR⁺/HER2⁻ advanced breast cancer (16). Moreover, abemaciclib plus fulvestrant has demonstrated significant progression-free survival (PFS) improvement even after disease progression on previous CDK4/6 inhibitor therapy, offering an additional treatment option in the post-CDK4/6 inhibitor setting (17). Yet, not all patients are eligible or able to access CDK4/6 inhibitors or oral SERDs due to cost, comorbidities, or intolerance. Thus, fulvestrant retains a pivotal role for those with ET-sensitive, indolent disease, and especially for nonvisceral metastases where the benefit is most pronounced.

FALCON’s strengths include its robust double-blind, randomized international design, long-term follow-up, and prespecified OS analysis. The trial provides some of the longest OS estimates for ET-naïve populations, with median OS near 4 years for both drugs. Limitations include its descriptive rather than powered OS analysis, the timing of therapy sequencing amidst evolving standards, and incomplete subsequent therapy capture post-study. Exploratory subgroup findings, particularly for nonvisceral and visceral populations, generate hypotheses that merit validation in larger, powered prospective cohorts. Real-world studies and meta-analyses, now involving thousands of patients, confirm that fulvestrant and other ET agents produce superior outcomes in nonvisceral vs. visceral metastatic disease. For example, Robertson et al.’s meta-analysis reports consistently longer OS among bone-only and soft tissue metastasis cohorts compared with liver and lung involvement (18).

As clinical trial evidence converges with real-world data, several key research avenues emerge (4,13):

• Identification and management of ESR1 mutations, which may predict ET resistance and help tailor optimal sequencing (e.g., oral SERDs for ESR1-mutant).
• Refinement of patient selection, incorporating molecular and genomic profiling to better stratify risk and optimize treatment.
• Ongoing phase III trials evaluating oral SERDs and their partner combinations, including CDK4/6 inhibitors, will define new standards for efficacy, safety, and patient-centered care.

The FALCON trial’s final OS analysis indicates that, while first-line fulvestrant and anastrozole did not show a statistically significant difference in OS in ET-naïve HR⁺/HER2⁻ advanced breast cancer, fulvestrant may confer a meaningful survival benefit for patients with nonvisceral metastases, reflecting a biologically indolent and endocrine-sensitive pattern. Its tolerability and favorable HRQOL underline its enduring value in the contemporary clinical armamentarium. Widespread use of fulvestrant, the rise of CDK4/6 inhibitors, and the imminent arrival of oral SERDs necessitate more sophisticated, personalized treatment algorithms rooted in both biological and clinical risk factors. The international oncology communities will rely increasingly on detailed trial and real-world evidence like FALCON to achieve precision care, improve patient outcomes, and guide the next generation of therapeutic innovations.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-2025-1-175/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-2025-1-175/coif). T.S. reports honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Novartis, MSD, Eisai, Taiho, Gilead, Pfizer, Chugai, Daiichi-Sankyo, Takeda, Kyowa-Kirin and Lily. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Gong Y, Liu YR, Ji P, et al. Impact of molecular subtypes on metastatic breast cancer patients: a SEER population-based study. Sci Rep 2017;7:45411. [Crossref] [PubMed]
2. Robertson JFR, Shao Z, Noguchi S, et al. Fulvestrant Versus Anastrozole in Endocrine Therapy-Naïve Women With Hormone Receptor-Positive Advanced Breast Cancer: Final Overall Survival in the Phase III FALCON Trial. J Clin Oncol 2025;43:1539-45. [Crossref] [PubMed]
3. Robertson JFR, Bondarenko IM, Trishkina E, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet 2016;388:2997-3005. [Crossref] [PubMed]
4. Di Leo A, Jerusalem G, Petruzelka L, et al. Final overall survival: fulvestrant 500 mg vs 250 mg in the randomized CONFIRM trial. J Natl Cancer Inst 2014;106:djt337. [Crossref] [PubMed]
5. Roberston JFR, Di Leo A, Fazal M, et al. Abstract PD5-09: Fulvestrant for hormone receptor-positive advanced breast cancer in patients with visceral vs non-visceral metastases: findings from FALCON, FIRST, and CONFIRM. Cancer Res 2018;78:PD5-09.
6. Ellis MJ, Llombart-Cussac A, Feltl D, et al. Fulvestrant 500 mg Versus Anastrozole 1 mg for the First-Line Treatment of Advanced Breast Cancer: Overall Survival Analysis From the Phase II FIRST Study. J Clin Oncol 2015;33:3781-7. [Crossref] [PubMed]
7. Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol 2010;28:4594-600. [Crossref] [PubMed]
8. Slamon DJ, Neven P, Chia S, et al. Ribociclib plus fulvestrant for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the phase III randomized MONALEESA-3 trial: updated overall survival. Ann Oncol 2021;32:1015-24. [Crossref] [PubMed]
9. Sledge GW Jr, Toi M, Neven P, et al. The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial. JAMA Oncol 2020;6:116-24. [Crossref] [PubMed]
10. Harbeck N, Franke F, Villanueva-Vazquez R, et al. Health-related quality of life in premenopausal women with hormone-receptor-positive, HER2-negative advanced breast cancer treated with ribociclib plus endocrine therapy: results from a phase III randomized clinical trial (MONALEESA-7). Ther Adv Med Oncol 2020;12:1758835920943065. [Crossref] [PubMed]
11. Wu Y, Han Y, Yu P, et al. Endocrine Therapy for Hormone Receptor-Positive Advanced Breast Cancer: A Nation-Wide Multicenter Epidemiological Study in China. Front Oncol 2020;10:599604. [Crossref] [PubMed]
12. Vergote I, Robertson JF, Kleeberg U, et al. Postmenopausal women who progress on fulvestrant ('Faslodex') remain sensitive to further endocrine therapy. Breast Cancer Res Treat 2003;79:207-11. [Crossref] [PubMed]
13. Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial. J Clin Oncol 2022;40:3246-56. [Crossref] [PubMed]
14. Neupane N, Bawek S, Gurusinghe S, et al. Oral SERD, a Novel Endocrine Therapy for Estrogen Receptor-Positive Breast Cancer. Cancers (Basel) 2024;16:619. [Crossref] [PubMed]
15. Oliveira M, Pominchuk D, Nowecki Z, et al. 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;25:1424-39. [Crossref] [PubMed]
16. Wang X, Zhao S, Xin Q, et al. Recent progress of CDK4/6 inhibitors' current practice in breast cancer. Cancer Gene Ther 2024;31:1283-91. [Crossref] [PubMed]
17. Kalinsky K, Bianchini G, Hamilton E, et al. Abemaciclib Plus Fulvestrant in Advanced Breast Cancer After Progression on CDK4/6 Inhibition: Results From the Phase III postMONARCH Trial. J Clin Oncol 2025;43:1101-12. [Crossref] [PubMed]
18. Robertson JFR, Di Leo A, Johnston S, et al. Meta-analyses of visceral versus non-visceral metastatic hormone receptor-positive breast cancer treated by endocrine monotherapies. NPJ Breast Cancer 2021;7:11. [Crossref] [PubMed]