The phase III FAMILY trial demonstrated a clinically meaningful and statistically significant improvement in PFS with fulvestrant maintenance therapy compared to capecitabine maintenance therapy in patients with HR + /HER2- MBC who achieved an objective response or disease control following first-line chemotherapy. The median PFS was 17.3 months (95% CI 12.7–23.3) for the fulvestrant group versus 9.0 months (95% CI 7.5–14.3) for the capecitabine group (hazard ratio 0.63, 95% CI 0.47–0.99, p = 0.003). The PFS benefit of fulvestrant maintenance therapy was consistent across most analyzed subgroups, further validating its clinical efficacy. Importantly, the benefit extended to tPFS, which reached 22.2 months with fulvestrant versus 14.4 months with capecitabine. Notably, nearly 60% of patients in this study presented with aggressive disease features, and in this subgroup, fulvestrant yielded superior PFS and tPFS compared to capecitabine. Additionally, patients in the fulvestrant group experienced numerically fewer AEs, underscoring its favorable safety profile. To our knowledge, this study for the first time directly compares fulvestrant with capecitabine as maintenance therapies in this specific patient population, providing a foundation for further research and clinical application.
The optimal sequencing of maintenance ET and chemotherapy in HR + /HER2- MBC remains a subject of debate. Our previous study found that no notable difference was observed in PFS and OS between chemotherapy and ET maintenance in this population.33 The phase II FANCY study suggested that fulvestrant 500 mg could be a promising maintenance therapy for HR + /HER2- MBC patients who exhibited no disease progression after first-line chemotherapy.32 Building upon these preliminary results, the FAMILY trial, for the first time, directly compared the efficacy of fulvestrant with capecitabine as a maintenance therapy after first-line chemotherapy. Encouragingly, this trial achieved its primary end point, with a clinically meaningful PFS improvement of 8.3 months in the fulvestrant group. Together, these findings highlight the growing role of endocrine maintenance therapy in improving outcomes for patients with HR + /HER2- MBC.
Several biological mechanisms may contribute to the observed efficacy of fulvestrant as maintenance therapy following chemotherapy compared with capecitabine. Fulvestrant functions as a selective estrogen receptor degrader that binds to the ER and promotes its proteasomal degradation, resulting in more complete and sustained inhibition of ER signaling.34 This mechanism may be particularly relevant after chemotherapy, as cytotoxic treatment can alter ER signaling dynamics and tumor biology. In addition, chemotherapy-induced tumor debulking and potential modulation of the tumor microenvironment may reduce the dominance of resistant subclones, thereby creating conditions under which residual hormone-dependent tumor cells remain susceptible to endocrine suppression. In this context, ER degradation by fulvestrant may more effectively suppress residual endocrine-responsive disease, leading to durable disease control in the maintenance setting. The biological mechanisms underlying these observations remain incompletely understood and warrant further investigation.
The RIGHT Choice study reaffirmed that first-line CDK4/6 inhibitors combined with ET are superior to chemotherapy in clinically aggressive HR + /HER2- ABC.10 However, in many parts of the world, particularly in developing countries, access to CDK4/6 inhibitors remains limited due to cost, reimbursement barriers, or drug availability. Against this backdrop, the present FAMILY trial addresses an important clinical gap. For patients achieving objective response or stable disease after a short course of chemotherapy (4-8 cycles), timely transition to endocrine maintenance, such as fulvestrant, offers a rational approach that balances efficacy, tolerability, and cost-effectiveness. In patients with clinically aggressive disease, this sequential strategy was associated with a clinically meaningful duration of disease control, as reflected by a median tPFS of 21.1 months. However, given differences in study design and patient populations, cross-trial comparisons should be interpreted with caution.
Treatment tolerability remains an important consideration for clinicians when selecting maintenance strategies. In this study, AEs in the fulvestrant group were consistent with its established safety profiles, with no unexpected AEs or new safety concerns reported.29,30,31 Similarly, AEs with capecitabine in this study were in line with previous data22,35,36. As expected, the overall incidence of AEs appeared to be lower for fulvestrant compared to capecitabine. Notably, in the fulvestrant group, no patients discontinued treatment due to AEs, whereas eight patients (7.6%) in the capecitabine group discontinued treatment, supporting the favorable tolerability of fulvestrant. Capecitabine was associated with a higher frequency of toxicities, particularly hand-foot syndrome, which could adversely impact quality of life during prolonged treatment. Previous studies have reported a higher susceptibility to fluoropyrimidine-related toxicities, including hand-foot syndrome, in Asian populations, which may be relevant when considering the tolerability of prolonged capecitabine exposure.36,37,38,39 In contrast, fulvestrant therapy was better tolerated. The incidence of injection-site pain observed with fulvestrant in this study was numerically higher than that reported in the FIRST study (16.2% and 5.9%, respectively).29 However, the incidence of arthralgia or joint disorders seemed to be numerically lower than that reported in previous studies, such as the FIRST study and the FALCON study (2.9%, 9.9%, and 16.7%, respectively).29,30 These findings underscore the excellent safety profile of fulvestrant, supporting its use as a maintenance therapy aimed at delaying relapse while preserving quality of life.
Alternative maintenance strategies for HR + /HER2- MBC are currently under active investigation, including the combination of ET with targeted therapies. Increasing attention has been given to the potential role of CDK4/6 inhibitors combined with ET as a maintenance strategy following first-line chemotherapy. The phase II AMICA trial reported encouraging efficacy and safety of the CDK4/6 inhibitor ribociclib plus ET in patients with HR + /HER2- MBC who achieved at least stable disease following first-line chemotherapy.40 Additionally, an ongoing phase II trial (NCT05979220) is currently evaluating the efficacy and safety of another CDK4/6 inhibitor, dalpiciclib, combined with letrozole, in this setting. Given the established efficacy and manageable safety profile of CDK4/6 inhibitors combined with fulvestrant in HR + /HER2- MBC,41,42,43,44 future studies may also consider exploring this combination as a potential maintenance strategy after first-line chemotherapy.
Our findings have important implications for real-world clinical practice. In many regions, chemotherapy remains the default first-line choice for patients with high tumor burden or visceral crisis. However, indefinite continuation of chemotherapy is not always necessary and may increase the risk of cumulative toxicity. The FAMILY trial demonstrates that, after disease control with short-course chemotherapy, switching to fulvestrant maintenance can achieve durable disease control, especially in clinically aggressive disease, while reducing toxicity and avoiding the financial and logistical barriers associated with immediate CDK4/6 inhibitor use. This strategy aligns well with current treatment goals in MBC and provides a practical, accessible, and cost-effective alternative for first-line care, especially in regions where CDK4/6 inhibitors are not routinely available or reimbursed.
Several limitations should be acknowledged. First, while the observed improvements in PFS are statistically and clinically significant, the OS data remain immature, limiting conclusions about long-term survival benefits. Continued follow-up is ongoing, and updated OS analyses will be performed at future prespecified data cutoffs to determine whether the observed PFS benefit translates into a survival advantage. Second, differences between the trial population and real-world clinical practice must be considered. Most patients in current practice receive ET plus a CDK4/6 inhibitor as initial treatment. Since this trial was initiated before the first approval of CDK4/6 inhibitors for MBC in China, patients pretreated with these agents were not included. Therefore, the findings of this study are most directly applicable to patients who receive first-line chemotherapy due to aggressive disease features or limited access to CDK4/6 inhibitors, and extrapolation to CDK4/6-pretreated populations should be made with caution. Future studies are warranted to evaluate the role of fulvestrant-based maintenance strategies following prior CDK4/6 inhibitor exposure. Third, the study population was relatively endocrine-sensitive, which may have favored endocrine-based maintenance and amplified the benefit observed with fulvestrant. Therefore, the findings are most applicable to this subgroup, and extrapolation to less endocrine-responsive populations should be made with caution. Another important limitation of the present report is the absence of mature quality-of-life (QoL) and patient-reported outcome (PRO) data. Additionally, the definition of “aggressive disease” used in this study is not fully standardized and is somewhat subjective. Prior capecitabine exposure in a subset of patients may have enriched for capecitabine-sensitive disease. Although balanced between arms, residual confounding due to intrinsic chemosensitivity cannot be excluded. As such, findings derived from these subgroup analyses should be interpreted with caution and considered exploratory. Finally, future studies should explore the underlying mechanisms that contribute to the differential effectiveness of fulvestrant versus capecitabine, such as molecular biomarkers that may predict response. Despite these limitations, this study provides strong evidence that short-course chemotherapy followed by fulvestrant maintenance is a feasible and effective strategy for HR + /HER2- MBC. This approach may be particularly beneficial for patients in regions where CDK4/6 inhibitors are not readily available or affordable.
In conclusion, the FAMILY trial provides robust evidence supporting the use of fulvestrant as an effective and well-tolerated maintenance therapy for patients with HR + /HER2- MBC who have achieved an objective response or disease control after first-line chemotherapy. This study highlights the potential of fulvestrant maintenance to improve outcomes while preserving quality of life, offering a valuable alternative to chemotherapy-based maintenance strategies. These findings offer significant implications for managing HR + /HER2- MBC, providing clinicians with an important option for long-term disease control, especially in settings where CDK4/6 inhibitors are inaccessible or cost-prohibitive. Further research is needed to confirm the long-term benefits of fulvestrant maintenance, explore its combination with other therapies (e.g., CDK4/6 inhibitors), and investigate biomarkers for individualized treatment strategies.
