The Value of Oral Selective Estrogen Receptor Degraders in Patients with HR-Positive, HER2-Negative Advanced Breast Cancer after Progression on ≥ 1 Line of Endocrine Therapy: Systematic Review and Meta-analysis

doi:10.21203/rs.3.rs-2854839/v1

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Research Article

The Value of Oral Selective Estrogen Receptor Degraders in Patients with HR-Positive, HER2-Negative Advanced Breast Cancer after Progression on ≥ 1 Line of Endocrine Therapy: Systematic Review and Meta-analysis

https://doi.org/10.21203/rs.3.rs-2854839/v1

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published 02 Jan, 2024

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Background: Currently, the value of oral selective estrogen receptor degraders (SERDs) for hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (aBC) after progression on ≥ 1 line of endocrine therapy (ET) remains controversial. We conducted a meta-analysis to evaluate progression-free survival (PFS) and safety benefits in several clinical trials.

Materials and methods: Cochrane Library, Embase, PubMed, and conference proceedings (SABCS, ASCO, ESMO, and ESMO Breast) were searched systematically and comprehensively. Random effects model or fixed effects models were used to assess pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for oral SERDs versus standard of care.

Results: A total of four studies involving 1,290 patients were included in our analysis. The hazard ratio (HR) of PFS showed that the oral SERDs regimen is better than the standard of carein patients with HR+/HER2- aBC after progression on ≥ 1 line of ET (HR: 0.75, 95% CI: 0.62-0.91, p = 0.004). In patients with ESR1 mutations, the oral SERDs regimen obtained better PFS than those treated with the standard of care (HR: 0.58, 95% CI: 0.47-0.71, p <0.00001). For patients with disease progression following previous use of CDK4/6 inhibitors, arms of the oral SERDs still obtain PFS profit versus the standard of care (HR: 0.75, 95% CI: 0.64-0.87, p = 0.0002).

Conclusions: Oral SERDs regimen has a significant PFS benefit compared to standard-of-care ET in patients with HR+/HER2- aBC after progression on ≥ 1 line of ET. In particular, we recommend oral SERDs as a preferred choice for those patients with ESR1m, and it could be a potential replacement for fulvestrant. Oral SERDs regimen also benefits after the progression of CDK4/6 inhibitors combined with endocrine therapy.

breast cancer

advance

HR+/HER2-

oral SERDs

meta-analysis

In the United States, approximately 60–70% of women with advanced breast cancer (aBC) are hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) ^[1–3]. Resistance to treatment, acquisition of novel mutations, and altered gene expression are the major challenges in the management of aBC ^{[4, 5]}. There are established guidelines for the first-line treatment for these patients, but the choice of second-line treatment has not yet reached a consensus ^[6].

endocrine therapy (ET), with either fulvestrant (Fulv) or aromatase inhibitors (AI), plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is the recommended first-line standard of care for patients with HR+/HER2- advanced breast cancer ^[7]. Compared with endocrine monotherapy, the combination can obtain a higher response rate and progression-free survival benefit ^[8–10]. But the development of resistance to the treatment of aBC is frequent, and its treatment is primarily palliative ^[11]. In general, there are three main strategies after the failure of CDK4/6i treatment: diversion to chemotherapy, endocrine therapy alone, or combined targeted therapy ^{[12, 13]}. Currently, there are no recommended guidelines for the optimal ranking of these options. In any case, ET is still an important treatment strategy.

Estrogen receptor 1 mutations (ESR1m) is one of the common mechanisms of endocrine resistance, which is up to 36% in metastatic breast cancers ^{[14, 15]}. Selective estrogen receptor degraders (SERDs) can bind to estrogen receptors and induce their degradation ^{[16, 17]}, considered one of the main ways to address endocrine resistance. Fulvestrant, as an intramuscular SERD, is not only the first-line or second-line treatment option for HR+/HER2- aBC ^{[18, 19]}, but patients with ESR1m are still sensitive to it ^[20–22]. In recent years, oral SERDs with their higher bioavailability and pharmacokinetics have been continuously developed to address the limitations of fulvestrant intramuscular formulations. However, the value of oral SERDs in patients with HR+/HER2- advanced breast cancer remains controversial. EMERALD ^[23] and SERENA-2 ^[24] showed positive results, while the other two clinical trials AMEERA-3 ^[25] and acelERA ^[26] failed the study endpoints.

The present meta-analysis aimed to assess the value of oral SERDs in patients with HR+/HER2- advanced breast cancer after progression on ≥ 1 line of endocrine therapy.

Search strategy and data extraction

The systematic review of literature and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines ^[27]. The corresponding PRISMA checklist is showed in Supplement 2. A systematic and comprehensive literature search was conducted using Embase, PubMed, and Cochrane Library. Conference proceedings from major oncology meetings (ASCO, SABCS, ESMO, and ESMO Breast) from 2020 up to January 2023 were also carefully reviewed. The following search string was used: “(breast OR mammary) AND (cancer OR carcinoma OR malignant OR neoplasm OR tumour) AND (hormone receptor-positive OR HR-positive OR HR OR estrogen receptor-positive OR ER OR ER-positive) AND (HER-2- OR HER2- OR ERBB2- OR HER-2 negative OR HER2 negative OR ERBB2 negative OR human epidermal growth factor receptor 2 negative) AND (metastasis OR metastases OR metastatic OR advanced OR recurrent OR stage IV) AND (oral selective estrogen receptor degrader OR SERD OR Giredestrant OR Camizestrant OR Imlunestrant OR Elacestrant OR Amcenestrant)”. Records from included studies were screened independently by two investigators. In case of disagreement, after consulting with the third investigators to reach a consensus.

When available, the following information was extracted: title, publication date, trial name, first author, country, sample size, study design, menopausal status, oral SERDs used, dose of oral SERDs, treatment regimens used in control arm, previous treatment regimen, ESR1m status, Hazard Ratio (HR), median progression-free survival (PFS) and side effects for each arm.

Study selection

Studies had to satisfy the following inclusion and exclusion criteria: (i) phase II or III randomized clinical trials (RCTs) including patients with HR+/HER2- aBC after progression on ≥ 1 line of ET; (ii) comparison of oral SERDs versus those treated with standard-of-care ET; and (iii) the publication provided PFS and HR for the experimental and control arms. Systemic reviews, case reports, single-arm studies, exploratory studies, and retrospective studies were excluded. If multiple publications were associated with the same clinical trial, only the latest data were extracted in our study.

Objectives

The primary objective of the study was to compare the efficacy of oral SERDs with standard-of-care ET in patients with HR+/HER2- aBC after progression on ≥ 1 line of ET. The secondary objective was to analyze the subgroup of the population that might benefit from oral SERDs. We planned the subgroup analysis for the following subgroups: patients with disease progression following previous use of CDK4/6 inhibitors or Fulv; patients with ESR1m; patients with visceral metastasis; comparing oral SERDS with fulvestrant; and comparing oral SERDS with fulvestrant in patients with ESR1m.

Statistical analysis

Global PFS was calculated using a random-effects model or fix-effects model and reported as pooled hazard ratios (HRS) with 95% confidence intervals (CIs). If 95% CI did not include 1.0 and two-side of threshold P < 0.05, the pooled HR was considered statistically significant. The I² value was employed for the heterogeneity of included studies. When I² > 50%, it is considered as significant heterogeneity, and the random-effects model was adopted; otherwise, the fixed-effects model was used. When heterogeneity was high in the pooled results, sensitivity analysis was performed after every single study was excluded. All statistical analysis methods were performed using Review Manager (version 5.3). The Cochrane Collaboration’s Risk of Bias tool in Review Manager (version 5.3) was employed to assess the risk of bias for each eligible study.

Study selection

A total of 251 potentially relevant manuscripts and 4 additional abstracts were sorted out by using the search string mentioned before. Of these, after reviewing the titles and abstracts, 241 manuscripts were excluded. We then performed a full-text review for the remaining 14 articles, 10 of which were excluded for non-conformity with the present inclusion criteria. Eventually, 4 articles from 4 trials were considered eligible for the meta-analysis. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flowchart is shown in Fig. 1.

Characteristics of studies

Finally, our study involved 4 clinical trials published between February 2022 and December 2022, focusing on different endocrine treatment regimens of HR+/HER2- advanced breast cancer, and including a total of 1,290 patients (Table 1). Oral SERDs arms include elacestrant (EMERALD), camizestrant75mg/camizestrant150mg (SERENA-2), amcenestrant (AMEERA-3), giredestrant (acelELA). Control arms included fulvestrant, anastrozole, letrozole, exemestane, tamoxifen. All trials compared oral SERDs to standard-of-care ET in patients with HR+/HER2- aBC after progression on ≥ 1 line of ET.

Table 1

Characteristics of eligible studies in the meta-analysis
Study	EMERALD	SERENA-2	AMEERA-3	acelELA
First author	Francois-Clement Bidard	Mafalda Oliveira	Sara M. Tolaney	Miguel Martin
Year of publication	2022	2022	2022	2022
Phase	Ⅲ	Ⅱ	Ⅱ	Ⅱ
Patients, n	477	220	290	303
Patients	Men or postmenopausal woman	Postmenopausal woman	Men or woman (any menopausal status)	Men or woman (any menopausal status)
Oral SERDs regimen / dose	Elacestrant / 400mg	Camizestrant / 75mg (A)^/ 150mg (B)^	Amcenestrant / 400mg	Giredestrant / 30mg
Standard-of-care ET	SOC	Fulvestrant	TPC	PCET
ESR1m, n	228	68	120	90
Prior CDK4/6i, %	Required, 100	Permitted, 49.6%	Permitted, 79.7	Permitted, 42
Allowed Prior Fulvestrant	Yes	NO	Yes	Yes
HR	0.70	0.58 (75mg)/ 0.67 (150mg)	1.051	0.81
95%CI	0.55–0.88	0.41–0.81 (75mg) / 0.48–0.92 (150mg)	0.789-1.40	0.60–1.01
Abbreviations: SOC: standard-of-care; TPC: treatment of physician’ choice; PCET: physician choice of endocrine monotherapy
^* SERENA-2 was divided into two cohorts because the comparisons were between two doses of camizestrant 75mg and 150mg.

Progression-free survival

In the whole population, patients with HR+/HER2- advanced breast cancer treated with oral SERDs significantly improved PFS compared to those treated with standard-of-care ET (HR: 0.75, 95% CI: 0.62–0.91, p = 0.004; I²: 52%, p = 0.08; Fig. 2A). For enrolled patients with disease progression following previous use of CDK4/6 inhibitors, oral SERDs regimen was significantly better than standard-of-care ET (HR: 0.75, 95% CI: 0.64–0.87, p = 0.0002; I²: 48%, p = 0.10; Fig. 2B). In HR+/HER2- ESR1m aBC, the two treatment regimens compared, namely oral SERDs resulted in a better PFS versus standard-of-care ET (HR: 0.58, 95% CI: 0.47–0.71, p < 0.00001; I²: 42%, p = 0.14; Fig. 2C). For enrolled patients with ESR1 mutations, arms of oral SERDs were significantly better than arms of fulvestrant (HR: 0.47, 95% CI: 0.36–0.62, p < 0.00001; I² : 0%, p = 0.41; Fig. 2D). For patients who had previously failed treatment with fulvestrant, oral SERDs as monotherapy was significantly superior to standard-of-care ET (HR : 0.67, 95% CI: 0.47–0.95, p = 0.02; I² : 0%, p = 0.93; Fig. 3A). In patients with visceral disease, arms of oral SERDs was significantly better than arms of standard-of-care ET (HR: 0.60, 95% CI: 0.48–0.74, p < 0.00001; I²: 33%, p = 0.22; Fig. 3B). Arms of oral SERDs were significantly better than arms of fulvestrant (HR: 0.65, 95% CI: 0.54–0.78, p < 0.00001; I²: 0%, p = 0.76; Fig. 3C).

Safety

Adverse events (AE) of Grade 3 or higher were more frequently in oral SERDs regimen than in standard-of-care ET (HR: 1.40, 95% CI: 1.03–1.90, p = 0.03; I²: 0%, p = 0.99; Fig. 4). The proportion of treatment-emergent adverse events (TEAEs) leading to discontinuation was 6.3% (Elacestrant ) vs. 4.4% (SOC) in EMERALD's two treatment arms; The most common adverse event was nausea. The proportion of drug discontinuation caused by TEAEs in the three treatment groups of SERENA-2 was 14.9% (camizestrant 75mg), 21.9% (camizestrant 150mg), 4.1% (standard-of-care ET), respectively; Common adverse events were photopsia and sinus bradycardia. In AMEERA-3, the proportion of TRAE ≥ Grade 3 was 4.9% in the experimental arm and 0.7% in the control arm; The most common adverse event was nausea. In acelELA, the incidence of AE ≥ Grade 3 was 12% (Giredestrant) vs. 8.6% (PCET); The most common adverse event was hepatotoxicity.

Bias assessment

In all included in the trials, the overall risk of bias was low (Supplement 1 Fig. 1). Since these trials were conducted with an open-label design, performance bias that did not affect the results may exist. There was no obvious publication bias (Supplement 1 Fig. 2–3).

Our study showed that the oral SERDs regimen was superior to standard-of-care ET in patients with HR+/HER2- advanced breast cancer after progression on ≥ 1 line of ET. However, the characteristics of these patients are complex, so it is crucial to select the characteristics of those patients who are likely to have sustained benefits.

Patients with ESR1m develop resistance to ET and exhibit worse overall survival ^[28–30]. Our meta-analysis showed that for patients with ESR1 mutations, arms of oral SERDs were significantly better than arms of standard-of-care ET. Surprisingly, in these four clinical trials, oral SERDs were able to achieve PFS benefits in ESR1m patients. In addition, patients with ESR1m showed a trend of OS improvement in Elacestrant (HR = 0.59; p = 0.03). AIs not only enhance the acquisition of ESR1 mutations in aBC, but patients with ESR1 mutations also show a worse prognosis in AI treatment ^[31]. However, patients with ESR1 mutations remain sensitive to fulvestrant ^[20–22]. As an intramuscular SERD, fulvestrant binds to estrogen receptors and induces their degradation ^{[16, 17]}, so it still plays a role in patients with ESR1 mutations. A pooled analysis of patients with ESR1 mutations in EFECT and SoFEA trials (115/383) found no significant difference in PFS in the Fulv group (3.9 months versus 4.1 months) ^[32–34]. However, the clinical utilization of Fulv is limited by its intramuscular formation. In the Elacestrant and SERENA-2 trials, the arms of oral SERDs were significantly better than the arms of fulvestrant (HR: 0.47, p < 0.00001). In addition, its better bioavailability and patient preference for oral medication may lead to better compliance. Patient tolerability of the drug also needs to be considered. The overall toxicity of oral SERDs was found to be greater in our analysis. However, considering that a proportion of patients in the control arms were on AIs and tamoxifen regimens, the toxicity of AIs and tamoxifen was lower than that of Fulv ^[35–37]. So it does not mean that oral SERDs are more toxic than Fulv. Moreover, treatment resistance to Fulv leading to disease progression remains a major concern for HR+/HER2- aBC. So both additional endocrine therapy and effective combination therapy are clinically necessary ^{[14, 15]}. Data from the Elacestrant and acelELA trials also support oral SERDs regimen for patients who failed Fulv therapy. Thus, oral SERDs are recommended in HR+/HER2- ESR1m aBC after ET ≥ 1 line progression, and oral SERDs could be a potential replacement for Fulv.

For HR+/HER2- aBC patients who progressed after first-line treatment with ET combined with CDK4/6i, the oral SERDs regimen also had a statistically significant PFS benefit. In the event of disease progression during the use of CDK4/6i, ET-based regimens remain an appropriate option ^{[12, 13]}. Patients' menopausal status, tolerance to drugs, and previous treatment regimens will affect the subsequent selection of endocrine agents ^[38]. These enrolled patients had used one or two ET regimens before, so it is still necessary to find new endocrine agents. Camizestrant may be a new option for those patients. The median PFS of the oral SERDs group was 7.2 (75mg) and 7.7 (150mg) months, respectively, while that of the Fulv group was only 3.7 months. Even in the subgroup with previous use of CDK4/6i, there was a significant improvement in PFS [median PFS 5.5 (75mg) and 3.8 (150mg) months VS 2.1 months]. However, the absolute benefit in Elacestrant was very small (median PFS 2.8 months VS 1.9 months). For those ESR1m aBC patients previously treated with CDK4/6i for ≥ 12 months, elacestrant had a median PFS of 8.6 months and SOC of 2.1 months, which was a clinically and statistically significant improvement. This suggests that a possible indication for elacestrant may be the duration of previous CDK4/6i ^[39]. In addition, for those patients with visceral metastasis, oral SERDs also showed their advantages (HR: 0.60, P < 0.00001). Endocrine therapy is the preferred option for HR + breast cancer patients even in the presence of visceral metastases ^[40]. Chemotherapy is recommended for patients with the visceral crisis. But chemotherapy is more toxic and will bring many side effects to patients ^[41]. In contrast, oral SERDs show better efficacy in patients with visceral metastasis, and can also reduce the serious side effects caused by chemotherapy.

Our study is the first to evaluate the value of oral SERDs in patients with HR+/HER2- aBC after progression on ≥ 1 line of endocrine therapy. The characteristics of the population that may benefit are also analyzed. There are several limitations to our study. First, this is not a network meta-analysis, and we cannot directly compare all drugs or drug combinations with each other. As a result, a certain degree of precision was lost. In addition, we could not evaluate the OS benefit due to the unavailability of data. However, these limitations are unavoidable at present.

Oral SERDs regimen has a significant PFS benefit compared to standard-of-care ET in patients with HR+/HER2- aBC after progression on ≥ 1 line of ET. In particular, we recommend oral SERDs as a preferred choice for those patients with ESR1m, and it could be a potential replacement for fulvestrant. Oral SERDs regimen also benefits after the progression of CDK4/6 inhibitors combined with endocrine therapy.

Author Contributions

Xiewei Huang, Yushuai Yu, Shiping Luo, and Wenfen Fu performed study design, article search, data collection, and analysis. Xiewei Huang and Yushuai Yu wrote the first draft of the manuscript. Jie Zhang and Chuangui Song reviewed the article. All authors participated in the commenting on the manuscript, read and approved the final manuscript.

Ethics approval and consent to participate

As the data used in this study were from previously published literature, ethical approval and informed consent were not required.

Consent for publication

No applicable.

Availability of data and materials

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

CompetingInterests

The author declared that there was no competing financial interests.

Funding Statement

The author statement in this manuscript preparation process, have not received any funds, grants or other support.

Acknowledgements

No applicable.

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The Value of Oral Selective Estrogen Receptor Degraders in Patients with HR-Positive, HER2-Negative Advanced Breast Cancer after Progression on ≥ 1 Line of Endocrine Therapy: Systematic Review and Meta-analysis

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Abstract

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Introduction

Materials and methods

Search strategy and data extraction

Study selection

Objectives

Statistical analysis

Results

Study selection

Characteristics of studies

Progression-free survival

Safety

Bias assessment

Discussion

Conclusion

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