Real-world data of fulvestrant as first-line treatment of postmenopausal women with estrogen receptor-positive metastatic breast cancer

Posted by zedie

Abstract

Goals of endocrine therapy for advanced breast cancer (ABC) include prolonging survival rates, maintaining the quality of life, and delaying the initiation of chemotherapy. We evaluated the effectiveness of fulvestrant as first-line in patients with estrogen receptor (ER)-positive ABC with relapse during or after adjuvant anti-estrogenic therapy in real-world settings. Retrospective, observational study involving 171 postmenopausal women with ER-positive ABC who received fulvestrant as first-line between January 2011 and May 2018 in Spanish hospitals. With a median follow-up of 31.4 months, the progression-free survival (PFS) with fulvestrant was 14.6 months. No differences were seen in the visceral metastatic (14.3 months) versus non-visceral (14.6 months) metastatic subgroup for PFS. Overall response rate and clinical benefit rate were 35.2% and 82.8%. Overall survival was 43.1 months. The duration of the clinical benefit was 19.2 months. Patients with ECOG performance status 0 at the start of treatment showed a significant greater clinical benefit rate and overall survival than with ECOG 1–2. Results in real-world settings are in concordance with randomized clinical trials. Fulvestrant continues to demonstrate clinical benefits in real-world settings and appears be well tolerated as first-line for the treatment of postmenopausal women with ER-positive ABC.

Introduction

Breast cancer (BC) is the most frequent type of carcinoma and leading cause of cancer-related mortality in women¹. Incidence and survival rates vary considerably among countries around the world due to diverse factors such as population structure (age, race, ethnicity), lifestyle, environment, socioeconomic status, genetics, disease stage at diagnosis, and healthcare (mammography use, access to high-quality care)². At diagnosis, most of patients present with early BC (EBC), however about 6–10% of cases have distant metastases³. Furthermore, approximately 30% of patients with EBC will develop metastatic BC (MBC) in the following months or years⁴. The expression of estrogen receptor (ER) and/or the progesterone receptor (PR) are used as prognostic factors in patients, and for predicting the response to adjuvant endocrine therapy, the main therapeutic option for ER-positive advanced breast cancer (ABC) patients^5,6. In this line, ER-positive BC comprise approximately 70% of all BC cases⁷. Goals of endocrine therapy for ABC include prolonging survival rates, maintaining the quality of life, and delaying, as possible, the initiation of chemotherapy⁸. Despite the proven efficacy of the endocrine therapy in these patients, one in three cases will develop resistance and, thus, disease progression⁹. Recently, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors combined with endocrine therapy have been recommended in first- or second-line treatment for patients with ER-positive/HER2-negative MBC¹⁰. However, there are still many patients who, due to comorbidities, elderly fragility or in order to avoid an added toxicity, could be suitable for receiving only hormonotherapy on this scenario. Thus, it seems relevant to know exactly what to expect from fulvestrant in first-line treatment of MBC with real-world data. Fulvestrant is a synthetic, selective ER antagonist that triggers the degradation of the ER protein¹¹. Several phase 3 trials have demonstrated the efficacy and safety of fulvestrant, in monotherapy and in combination with other agents, for the treatment of ER-positive ABC. One of them is the international FALCON trial that compared the efficacy of fulvestrant with an aromatase inhibitor, anastrozole, in 462 ER-positive ABC patients who had not received previously an endocrine therapy¹². Fulvestrant showed superior efficacy in terms of progression-free survival (PFS, 16.6 months; 95% confidence interval, 95% CI 13.8–21.0 months) than anastrozole (13.8 months, 95% CI 12.0–16.6 months), and similar rates of adverse events (AEs). Real-world evidence is an important step for completing data obtained from randomized clinical trials¹³. Therefore, the objective of the present study was to evaluate the effectiveness of fulvestrant as first-line for the treatment of patients with ER-positive MBC with relapse during or after the completion of adjuvant anti-estrogenic therapy in real-world settings.

Material and methods

This retrospective, observational study involved postmenopausal women with ER-positive ABC who received fulvestrant as first-line between January 2011 and May 2018. A total of 11 centers across Spain participated in the study. Inclusion criteria were: Informed consent written and signed prior to any specific study of procedures (in the case of patients who died at the time of inclusion, there were no signed informed consent, so the researcher assumed responsibility for data protection and confidentiality); postmenopausal women, according to NCCN definition, i.e. those who underwent a previous bilateral oophorectomy, aged ≥ 60 years, or aged < 60 years and amenorrhea for ≥ 12 months in the absence of chemotherapy, tamoxifen, toremifene or ovarian suppression, as well as follicle-stimulating hormone and estradiol¹⁴; diagnosis of MBC with histological/cytological confirmation; positive hormone receptor status (ER-positive and/or PgR-positive) from primary or metastatic tumor tissue receptors; Eastern Cooperative Oncology performance status (ECOG PS) score of 0, 1 or 2 at the time of starting fulvestrant¹⁵; having experienced recurrence during or after completing the adjuvant anti-estrogenic therapy; and receiving fulvestrant 500 mg as first-line, i.e. subsequently to the recurrence. Exclusion criteria included: Patients who were not available for the signature date of informed consent (in the case of patients alive at the time of study inclusion) or later than the date of baseline study; having received fulvestrant previously; having received any other therapy (different to fulvestrant) after the recurrence; previous neoplasia (other than BC or treatment for basal or squamous cell carcinoma of the skin or cervical carcinoma in situ) unless it has been treated curatively with no evidence of disease in the last 5 years; and patients with HER2-positive BC (3-positive HER2 overexpression by immunohistochemistry or positive gene amplification by fluorescence in situ hybridization or similar techniques). The status of ER and PgR was evaluated by using an immunohistochemical analysis with antibodies against ER and PgR, respectively¹⁶. The classification of Luminal A and B was also established according to immunohistochemistry, i.e. luminal A (ER-positive, PgR-positive, HER2-neagtive, Ki67% ≤ 20), and luminal B (other cases)^16,17. Patients were followed-up for a minimum period of 12 months were in accordance with Declaration of Helsinki and approved by the Ethics Committee of Hospital Universitario San Cecilio (Spain).

Studied variables

The effectiveness of fulvestrant was determined in terms of PFS. The PFS was defined as the elapsed time between start of treatment with fulvestrant and disease progression or death, by any cause. Secondary endpoints included: overall survival (OS), overall response rate (ORR), duration of the response, clinical benefit rate (CBR), duration of the clinical benefit (DoCB), response to subsequent treatments, progression-free rate (PFR), safety, and tolerability. The OS was defined as the elapsed time between start of treatment with fulvestrant and death, by any cause. At the time of data collection, data from patients who were alive without progression were censored for the survival analysis on the date of their last follow-up. The ORR was calculated as the sum of complete response (CR) and partial response (PR); whereas CBR as CR, PR and stable disease (SD) persisting for ≥ 24 weeks. The PFR was defined as the proportion of patients who remained with no disease progression or death. The AEs were reported by using the Common Terminology Criteria for Adverse Events (CTCAE) V4.0. Primary endocrine resistance was defined as the relapse occurrence while on the first 2 years of adjuvant endocrine treatment; secondary endocrine resistance as the relapse occurrence while on adjuvant endocrine treatment but after the first 2 years; and hormone-sensitive patients as the relapse occurrence after 1 year of finishing 5 years on adjuvant endocrine treatment.

Statistical analysis

Quantitative variables were expressed as median, interquartile range (IQR) or 95% CI; whereas qualitative ones as absolute and relative frequencies. Survival analyses were carried out by following Kaplan–Meier methodology. Comparison of survival curves between subgroups was performed using Log-rank tests. Comparison of variables between subgroups was carried out using parametric (T test or analysis of variance, ANOVA), or nonparametric (Mann–Whitney U or Kruskal–Wallis) tests, when appropriate. Statistical significance was established when p ≤ 0.05. All statistical procedures were performed using SAS software 9.4.

Ethics approval

Procedures were in accordance with Declaration of Helsinki and approved by the Ethics Committee of Hospital Universitario San Cecilio (Spain).

Consent to participate

All patients signed the informed consent to participate before being included in the study.

Results

Study population

A total of 171 patients were recruited in the study; however, 128 fulfilled the inclusion criteria. A patient flowchart is shown in Fig. 1. Patients had a median age of 69.2 years (IQR, 59.0–78.9 years) at the time of study inclusion. Ductal carcinoma (76.6% of patients) was the most predominant histological type of the EBC; predominantly of grade 2 (moderately differentiated, 59.8% of patients). Demographic and clinical characteristics of patients are shown in Table 1. At the time of EBC diagnosis, 68.8% of patients were ER-positive, 78.9% PgR-positive, 68.6% showed a low Ki67 proliferation index (≤ 20%). None of the patients presented with de novo metastatic disease. The median time from diagnosis of early disease to ABC was 6.8 years (IQR, 3.7–10.5 years). Biopsy for metastatic location was performed in 47.7% of patients. A total of 51.6% of patients developed metastases in non-visceral locations (41.5% in bones, 10.2% in local relapse). At the time of starting treatment with fulvestrant, 93.0% of patients had ECOG PS 0–1. The median duration of the treatment with fulvestrant was 14.0 months (IQR, 6.9–26.6 months).

Table 1 Demographic and clinical characteristics of patients.

Effectiveness outcomes

With a median follow-up period of 31.4 months, the median PFS with fulvestrant was 14.6 months (95% CI 10.9–19.9 months; Fig. 2). Effectiveness outcomes considering subgroups of patients are shown in Table 2. No differences in PFS were found regarding type of cancer, Ki67 proliferation index, ECOG PS at the start of treatment with fulvestrant, metastasis location, adjuvant treatments, and endocrine resistance. However, patients ER-positive/ PgR-positive in ABC (on biopsy, median 23.2 months; 95% CI 11.5–25.2 months) showed a significant longer PFS than ER-positive /PgR-negative (median 16.1 months; 95% CI 1.6–21.5 months; p = 0.048). The CBR was 82.8% (95% CI 75.1–88.9%). Significant differences in CBR were found regarding: hormone receptors (at EBC; 86.1% for ER-positive/ PgR-positive versus 70.4% for ER-positive /PgR-negative; p = 0.054); hormone receptors (at ABC, on biopsy; 95.4% for ER-positive / PgR-positive versus 53.8% for ER-positive /PgR-negative; p = 0.001); and ECOG PS at the start of treatment (90.9% for ECOG 0 versus 74.2% for ECOG 1–2; p = 0.012). The median of DoCB with fulvestrant was 19.2 months (95% CI 14.0–24.1 months). The ORR was 35.2% (95% CI 26.9–44.1%). No significant differences in DoCB or ORR were found regarding subgroups (data not shown). The median OS from the start of the fulvestrant treatment was 43.1 months (95% CI 35.0–52.3 months; Fig. 3). Patients with ECOG PS 0 at the start of treatment (median 47.6 months; 95% CI 35.7–70.2 months) showed a significant longer OS than those with ECOG PS 1–2 (median 36.5 months; 95% CI 26.9–50.1 months; p = 0.024). No differences in OS were found regarding type of cancer, hormone receptor, Ki67 proliferation index, metastasis location, adjuvant treatments, and endocrine resistance. The PFR was 26.6% (95% CI 19.1–35.1%). No differences in PFR were found regarding subgroups (data not shown). A total of 96 patients initiated a subsequent treatment after disease progression with fulvestrant: chemotherapy (46 patients, 47.9%); hormonal therapy (46 patients, 47.9%), and radiotherapy (4 patients; 4.2%). After this treatment, 78.1% were free of progression: 73.9% in patients with chemotherapy, 75.0% with radiotherapy, and 82.6% with hormonal therapy. A total of 42 patients reported a second subsequent treatment: Chemotherapy (64.3%), hormonal therapy (26.2%), and radiotherapy (9.5%).

Table 2 Efficacy outcomes considering subgroups of patients.

Safety profile

The number of evaluable patients for safety analyses was 139. Of them, 93 patients (66.9%) experienced a total of 553 AEs.12 patients (8.6%) reported 14 serious AEs no related with the treatment: respiratory/thoracic/mediastinal disorders (4 cases), gastrointestinal disorders (2 cases), hepatobiliary disorders (2 cases), infections and infestations (2 cases), musculoskeletal and connective tissue disorders (2 cases), injury/poisoning/procedural complications (1 case), and metabolism and nutrition disorders (1 case). The most prevalent AEs were: musculoskeletal and connective tissue disorders (53 patients, 38.1%), asthenia (48, 34.5%), injection site reactions (30, 21.6%), nausea (18, 12.9%), decreased appetite (18, 12.9%), and diarrhea (15, 10.8%). 32 AEs (5.8% of the total) were causal relationship: Injection site reaction or hypersensitivity (7); asthenia (7); gastrointestinal disorders (6); musculoskeletal and connective tissue disorders (3); blood and lymphatic system disorders (2); respiratory- thoracic and mediastinal disorders (2); headache (1); fatigue (1); tachycardia (1); nail disorder (1); and decreased appetite (1) (Table 3). One patient died because of a serious AE (grade 5 hemoptysis) not related with the fulvestrant.Table 3 Incidence of most frequent adverse events.

Discussion

The efficacy and safety of fulvestrant is mainly based on results from 3 pivotal randomized clinical trials^{12,18,19,20,21,22}. In the aforementioned phase III FALCON study, involving women who did not receive a previous endocrine therapy, the CBR was 78% with fulvestrant and 74% with anastrozole¹². The median DoCB was also numerically longer with fulvestrant (22.1 months; 95% CI 18.5–24.9 months versus 19.1 months; 95% CI 16.5–20.5 months)¹². The OS was not calculated due to insufficient follow-up at the time of data cut-off, however a lower percentage of women who died was observed in the fulvestrant group (29%) than with anastrozole (32%). The most frequent AE associated to fulvestrant were arthralgia (38 patients, out of 228 evaluable ones for safety, 17%), hot flush (26 patients, 11%), fatigue (26 patients, 11%), nausea (24 patients, 11%), and back pain (21 patients, 9%). The Fulvestrant First-Line Study Comparing Endocrine Treatments (FIRST) phase II trial compared the efficacy and safety of fulvestrant 500 mg and anastrozole 1 mg as first-line endocrine therapy in 205 postmenopausal women with ABC^18,19,20. With fulvestrant, ORR (36%) and CBR (72.5%) were similar than with anastrozole (35.5% and 67.0%, respectively). Although the median DoCB had not been reached at primary data cut-off, the tendency favored fulvestrant, with respect to anastrozole¹⁸. A subsequent follow-up analysis (when 79.5% of patients had discontinued the study treatment) revealed a significant longer time to progression with fulvestrant (23.4 months) than anastrozole (13.1 months), i.e. 34% reduced the progression risk¹⁹. Moreover, the OS was improved with fulvestrant (54.1 months versus 48.4 months with anastrozole)²⁰. Regarding safety, gastrointestinal disturbances (28 patients, out of 101 evaluated ones, 27.7%), joint disorders (14 patients, 13.9%), and hot flashes (13 patients, 12.9%) were the most prevalent AEs related to fulvestrant¹⁸. Finally, the phase III Comparison of Faslodex Recurrent or Metastatic Breast Cancer (CONFIRM) trial compared the efficacy and safety of fulvestrant 250 and 500 mg in 736 postmenopausal women with ABC^21,22. Fulvestrant 500 mg was used in both first- and second- lines in CONFIRM population. The ORR and CBR with fulvestrant 250 mg were 10.2 and 39.6 months, respectively; and 9.1 months and 45.6 months with fulvestrant 500 mg²¹. Fulvestrant 500 mg showed a significant longer PFS (6.5 months) versus 250 mg (5.5 months). The median OS was 22.3 and 26.4 months for fulvestrant 250 and 500 mg, respectively²². Most prevalent grade ≥ 3 AEs with fulvestrant 250 mg were: joint disorders (8 patients, out of 374 evaluable ones, 2.1%), thromboembolic events (4 patients, 1.1%), and ischemic cardiovascular disorders (3 patients, 0.8%); whereas with fulvestrant 500 mg were joint disorders (8 patients, out of 361 evaluable, 2.2%), and gastrointestinal disturbances (8 patients, 2.2%)²¹.

Results from our present real-world study are in concordance with pivotal trials^{12,18,19,20,21,22}: CBR (82.8%, slightly higher than 78% in FALCON trial)¹², DoCB (19.2 months, slightly reduced than 22.1 months in FALCON trial); PFS (14.6 months, similar to 16.6 months in FALCON trial), and OS (43.1 months, slightly reduced than 54.1 months in FIRST trial²¹. The combination of a CDK4/6inhibitor (such as palbociclib, ribociclib or abemaciclib) with endocrine therapy is the standard treatment for ER-positive/HER2-negative MBC¹⁰. Recent studies have demonstrated that the combination of a CDK4/6 inhibitor and fulvestrant improves OS in patients with hormone receptor-positive, HER 2-negative MBC, either after failure of endocrine therapy (and irrespective of menopausal status), and as first- or second-line therapy in postmenopausal women^23,24. Our present study provides real-world efficacy data from fulvestrant (a high CBR and PFS of 14 months) that can be useful for patients who are not candidate for receiving a CDK4/6 inhibitor, due to possible added toxicity of the inhibitor, other comorbidities, elderly fragility, or that the patient is not able of undergoing the frequent clinical and hematologic controls required for CDK4/6 inhibitors. Indeed, ESMO has recommended for the management of MBC patients during the COVID-19 pandemic that, when combining CDK4/6 inhibitors with endocrine therapies, it is needed to consider risks of neutropenia, and that the patient requires close monitoring of symptoms of infection^25,26. And so, considering the option of postponing a line of CDK4/6 inhibitors, for bone only, low burden, de novo metastatic disease, particularly in the elderly. Therefore, nowadays, the results from our study are relevant because an important group of patients could benefit from fulvestrant in first-line of MBC treatment.

On the other hand, there are no currently clinical tools that predict which patients may benefit from diverse endocrine therapies²⁷. The CONFIRM and FIRST trials also evaluated PFS according to the characteristics of patients; however, the treatment efficacy was consistent across subgroups^19,20,21. By contrast, FALCON study revealed that visceral involvement showed a significant differentiation in PFS (fulvestrant versus anastrozole)¹². In patients receiving fulvestrant, PFS was 22.3 months (95% CI 16.6–32.8 months) for those with non-visceral disease, and 13.8 months (95% CI 11.0–16.5 months) with visceral involvement. In our real-world study, visceral disease was not associated with a differential effectiveness of fulvestrant. Nevertheless, ECOG PS 0 at the start of treatment was associated with greater CBR and OS, compared with ECOG 1–2.

Regarding the safety profile, reported AEs were in line with observed previously in clinical trials^{12,18,19,20,21,22}. Most frequent AEs included those concerning the musculoskeletal and connective tissue, administration site, and gastrointestinal disorders. The AEs did not raise any major concerns. The main limitation of the study derived from its retrospective design; providing only available data.

Conclusion

Results in real-world settings are in concordance with previously observed in randomized clinical trials. Moreover, fulvestrant continues to demonstrate clinical benefits in real-world settings, and appears well tolerated as first-line for the treatment of postmenopausal women with ER-positive ABC.

Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer

Posted by zedie

Abstract

BACKGROUND

The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor palbociclib, in combination with fulvestrant therapy, prolongs progression-free survival among patients with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer. We report the results of a prespecified analysis of overall survival.

METHODS

We randomly assigned patients with hormone-receptor–positive, HER2-negative advanced breast cancer who had progression or relapse during previous endocrine therapy to receive palbociclib plus fulvestrant or placebo plus fulvestrant. We analyzed overall survival; the effect of palbociclib according to the prespecified stratification factors of presence or absence of sensitivity to endocrine therapy, presence or absence of visceral metastatic disease, and menopausal status; the efficacy of subsequent therapies after disease progression; and safety.

RESULTS

Among 521 patients who underwent randomization, the median overall survival was 34.9 months (95% confidence interval [CI], 28.8 to 40.0) in the palbociclib–fulvestrant group and 28.0 months (95% CI, 23.6 to 34.6) in the placebo–fulvestrant group (hazard ratio for death, 0.81; 95% CI, 0.64 to 1.03; P=0.09; absolute difference, 6.9 months). CDK4/6 inhibitor treatment after the completion of the trial regimen occurred in 16% of the patients in the placebo–fulvestrant group. Among 410 patients with sensitivity to previous endocrine therapy, the median overall survival was 39.7 months (95% CI, 34.8 to 45.7) in the palbociclib–fulvestrant group and 29.7 months (95% CI, 23.8 to 37.9) in the placebo–fulvestrant group (hazard ratio, 0.72; 95% CI, 0.55 to 0.94; absolute difference, 10.0 months). The median duration of subsequent therapy was similar in the two groups, and the median time to the receipt of chemotherapy was 17.6 months in the palbociclib–fulvestrant group, as compared with 8.8 months in the placebo–fulvestrant group (hazard ratio, 0.58; 95% CI, 0.47 to 0.73; P<0.001). No new safety signals were observed with 44.8 months of follow-up.

CONCLUSIONS

Among patients with hormone-receptor–positive, HER2-negative advanced breast cancer who had sensitivity to previous endocrine therapy, treatment with palbociclib–fulvestrant resulted in longer overall survival than treatment with placebo–fulvestrant. The differences in overall survival in the entire trial group were not significant.

In 2018, approximately 266,000 new cases of breast cancer are estimated to occur in women in the United States, with 41,000 deaths.¹ Of these, hormone-receptor–positive breast cancer is the most common disease subtype.² The cyclin-dependent kinases 4 and 6 (CDK4/6) are key promoters of tumor growth in hormone-receptor–positive breast cancer, cooperating with estrogen-receptor pathway activation.^3,4 Preclinical models of hormone-receptor–positive breast cancer were highly sensitive to the CDK4/6 inhibitor palbociclib (Ibrance, Pfizer),⁴ and in a subsequent phase 2 study (Palbociclib: Ongoing Trials in the Management of Breast Cancer [PALOMA]–1), palbociclib resulted in a progression-free survival benefit in patients with previously untreated, estrogen-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer.⁵ Subsequently, the randomized, phase 3 trial PALOMA-2 confirmed that palbociclib substantially prolonged progression-free survival, in combination with letrozole, as first-line therapy for estrogen-receptor–positive, HER2-negative advanced breast cancer (hazard ratio for disease progression or death, 0.58; 95% confidence interval [CI], 0.46 to 0.72).⁶

In the phase 3 trial PALOMA-3, we assessed whether treatment with palbociclib, in combination with fulvestrant, prolonged progression-free survival among patients with hormone-receptor–positive, HER2-negative advanced breast cancer who had disease progression after previous endocrine therapy. The primary aim of the trial was met, with the trial showing significantly longer progression-free survival with combination palbociclib–fulvestrant therapy than with placebo–fulvestrant (median, 11.2 months [95% CI, 9.5 to 12.9] vs. 4.6 months [95% CI, 3.5 to 5.6]; hazard ratio for disease progression or death, 0.50; 95% CI, 0.40 to 0.62; absolute difference, 6.6 months).^7-9

Palbociclib and other CDK4/6 inhibitors in combination with endocrine therapy have become a standard of care on the basis of prolonged progression-free survival.^5,10,11 However, long-term data regarding the effect of palbociclib on overall survival and the efficacy of subsequent therapy have been limited. Here, we report the results of a prespecified analysis of the PALOMA-3 trial in which we assessed the effect of palbociclib on overall survival and the efficacy of therapies administered after disease progression.

Methods

TRIAL DESIGN AND PATIENTS

We conducted this prospective, international, randomized, double-blind, placebo-controlled, phase 3 trial to compare treatment with palbociclib–fulvestrant with placebo–fulvestrant in women with hormone-receptor–positive, HER2-negative advanced breast cancer who had disease progression after previous endocrine therapy. Patients were randomly assigned, in a 2:1 ratio, to receive either palbociclib (at a dose of 125 mg, administered orally, once daily for 21 consecutive days, followed by 7 days off, to comprise a complete cycle of 28 days) plus fulvestrant (at a dose of 500 mg, administered as an intramuscular injection according to standard of care, every 14 days for the first three injections and then every 28 days) or placebo plus fulvestrant. Crossover between the two groups was not permitted.

Women were enrolled regardless of menopausal status; postmenopausal women were at least 60 years of age, had undergone bilateral oophorectomy, or were younger than 60 years of age and had had a cessation of regular menses for at least 12 consecutive months. Premenopausal or perimenopausal patients were required to receive concurrent goserelin for at least 4 weeks before the start of the trial intervention and to continue receiving it every 28 days for the duration of the trial intervention.

Randomization was stratified according to the presence or absence of documented sensitivity to previous endocrine therapy, the presence or absence of visceral metastatic disease, and menopausal status at trial entry. Sensitivity to previous endocrine therapy was defined as either a documented clinical benefit (complete response, partial response, or stable disease for ≥24 weeks) from at least one previous endocrine therapy regimen in the context of metastatic disease or the receipt of at least 24 months of adjuvant endocrine therapy before recurrence. Detailed methods of this trial have been reported previously.^7,8 The protocol, with the statistical analysis plan, is available with the full text of this article at NEJM.org.

END POINTS

The primary end point, investigator-assessed progression-free survival, was reported previously.^7,8 Overall survival, a prespecified key secondary end point, was defined as the time from randomization to death from any cause. Exploratory analyses included the investigator-assessed time receiving subsequent therapy (i.e., the time from randomization to the end of the immediate subsequent line of therapy after disease progression) and time from randomization to the receipt of chemotherapy. Safety data were updated with additional follow-up time.

OVERSIGHT

The trial was designed by an academic steering committee that included representatives of the sponsor (Pfizer). Data were gathered by representatives of the sponsor. All the authors confirm that the trial conformed to the protocol and attest to the accuracy and completeness of the data. All the authors and participating institutions have agreements with the sponsor regarding confidentiality of the data. The first author wrote the first draft of the manuscript. All the authors had full access to the data and were involved in interpreting the data, in writing and reviewing subsequent drafts of the manuscript, and in making the decision to submit the manuscript for publication. A professional medical writer provided editorial assistance and was paid by the sponsor. AstraZeneca provided fulvestrant and had no involvement with the data collection or analysis or with any aspect of the manuscript preparation.

The trial was approved by the institutional review board at each site, and all the patients provided written informed consent before enrollment. The trial was conducted according to the principles of Good Clinical Practice and the Declaration of Helsinki. The conduct of the trial was monitored by an academic steering committee.

STATISTICAL ANALYSIS

The median overall survival among women with advanced or metastatic breast cancer who are treated with fulvestrant monotherapy was assumed to be 24 months. The trial was powered for its primary end point, progression-free survival. The planned final analysis of overall survival was performed after approximately 60% data maturity (i.e., when death had occurred in 60% of the 521 patients who had undergone randomization), with one interim analysis of overall survival conducted at the time of the interim analysis of progression-free survival, when 28 deaths had occurred, and one interim analysis conducted when 112 deaths had occurred. The family-wise error rate was protected at the one-sided 0.025 level, with a hierarchical testing strategy between progression-free survival and overall survival.^12,13 The median overall survival was estimated with the use of the Kaplan–Meier method, and the significance was determined with the use of a one-sided log-rank test with stratification according to presence or absence of sensitivity to previous endocrine therapy and the presence or absence of visceral metastases at randomization in the intention-to-treat population. All the P values reported herein are two-sided. The prespecified significance threshold was a two-sided P value of 0.047, which was adjusted for the planned interim analyses. The rank-preserving structural-failure time method was used as a sensitivity analysis to evaluate the effect of crossover to receive a CDK4/6 inhibitor in the placebo–fulvestrant group after the completion of the trial intervention. The rank-preserving structural-failure time analysis is based on the intention-to-treat population and can provide a more accurate estimation of the treatment effect by correcting for crossover between groups.^14,15

Results

PATIENTS

A total of 521 patients were enrolled between October 7, 2013, and August 26, 2014 (Fig. S1 in the Supplementary Appendix, available at NEJM.org). A total of 347 patients were randomly assigned to the palbociclib–fulvestrant group and 174 to the placebo–fulvestrant group (intention-to-treat population). A total of 345 patients in the palbociclib–fulvestrant group and 172 in the placebo–fulvestrant group received at least one dose of the assigned intervention (safety population).

Double-blinding was maintained after both the primary analysis and the interim analysis. After a request from the investigator, unblinding occurred in 12 patients (3%) who received palbociclib and in 18 (10%) who received placebo. Most of these unblinding events (in 7 patients in the palbociclib–fulvestrant group and in 17 in the placebo–fulvestrant group) occurred after disease progression.

OVERALL SURVIVAL

Figure 1.Overall Survival in the Overall Population and According to Subgroup.

The data regarding overall survival were analyzed at a cutoff date of April 13, 2018, with a median follow-up of 44.8 months and 60% data maturity (310 deaths among 521 patients). A total of 201 deaths occurred in the palbociclib–fulvestrant group, and 109 deaths in the placebo–fulvestrant group. The median overall survival was 34.9 months (95% CI, 28.8 to 40.0) in the palbociclib–fulvestrant group and 28.0 months (95% CI, 23.6 to 34.6) in the placebo–fulvestrant group. The stratified hazard ratio for death was 0.81 (95% CI, 0.64 to 1.03; P=0.09) (Figure 1A). The unstratified hazard ratio was 0.79 (95% CI, 0.63 to 1.00). The estimated rate of overall survival at 3 years in the Kaplan–Meier analysis was 50% (95% CI, 44 to 55) in the palbociclib–fulvestrant group and 41% (95% CI, 33 to 48) in the placebo–fulvestrant group.Figure 2.Overall Survival According to Patients’ Sensitivity to Previous Endocrine Therapy.

Subgroup analyses of overall survival were performed in prespecified subgroups (Figure 1B). The three prespecified stratification factors were the presence or absence of sensitivity to previous endocrine therapy, the presence or absence of visceral metastatic disease, and menopausal status. Among 410 patients with documented sensitivity to previous endocrine therapy, the median overall survival was 39.7 months (95% CI, 34.8 to 45.7) in the palbociclib–fulvestrant group and 29.7 months (95% CI, 23.8 to 37.9) in the placebo–fulvestrant group (hazard ratio for death, 0.72; 95% CI, 0.55 to 0.94) (Figure 1B and Figure 2A). Among 111 patients without documented sensitivity to previous endocrine therapy (also referred to as intrinsic endocrine resistance), the median overall survival was 20.2 months (95% CI, 17.2 to 26.4) in the palbociclib–fulvestrant group and 26.2 months (95% CI, 17.5 to 31.8) in the placebo–fulvestrant group (hazard ratio, 1.14; 95% CI, 0.71 to 1.84; P=0.12 for interaction) (Figure 1B and Figure 2B). In the updated analysis of PALOMA-3, which was conducted at a data cutoff of October 23, 2015, patients with sensitivity to previous endocrine therapy had progression-free survival that was 7.8 months longer in the palbociclib–fulvestrant group than in the placebo–fulvestrant group (hazard ratio for disease progression or death, 0.46; 95% CI, 0.36 to 0.59), whereas patients with intrinsic endocrine resistance had progression-free survival that was 2.3 months longer (hazard ratio, 0.69; 95% CI, 0.43 to 1.09) (Fig. S2 in the Supplementary Appendix).

Among 311 patients with visceral metastatic disease, the median overall survival was 27.6 months (95% CI, 24.4 to 31.2) in the palbociclib–fulvestrant group and 24.7 months (95% CI, 20.8 to 31.8) in the placebo–fulvestrant group (hazard ratio for death, 0.85; 95% CI, 0.64 to 1.13) (Figure 1B). Among 210 patients without visceral metastatic disease, the median overall survival was 46.9 months (95% CI, 39.3 to could not be estimated) in the palbociclib–fulvestrant group and 35.4 months (95% CI, 24.6 to could not be estimated) in the placebo–fulvestrant group (hazard ratio, 0.69; 95% CI, 0.46 to 1.04; P=0.44 for interaction) (Figure 1B).

Among 413 postmenopausal patients, the median overall survival was 34.8 months (95% CI, 28.8 to 40.1) in the palbociclib–fulvestrant group and 27.1 months (95% CI, 22.8 to 32.1) in the placebo–fulvestrant group (hazard ratio for death, 0.73; 95% CI, 0.57 to 0.95) (Figure 1B, and Fig. S3A in the Supplementary Appendix). Among 108 premenopausal or perimenopausal patients, the median overall survival was 38.0 months (95% CI, 24.4 to could not be estimated) in the palbociclib–fulvestrant group and 38.0 months (95% CI, 22.2 to could not be estimated) in the placebo–fulvestrant group (hazard ratio, 1.07; 95% CI, 0.61 to 1.86; P=0.25 for interaction) (Figure 1B, and Fig. S3B in the Supplementary Appendix).

An exploratory subgroup analysis evaluated overall survival according to ESR1 and PIK3CA mutation status, as assessed in baseline circulating tumor DNA. The median overall survival was longer with palbociclib–fulvestrant than with placebo–fulvestrant among patients with baseline ESR1 mutations than among those without such mutations (absolute difference, 11.0 months among patients with ESR1 mutations and 4.7 months among those without such mutations; P=0.60 for interaction) (Figure 1B). The absolute between-group differences in overall survival were similar among patients with baseline PIK3CA mutations and those without such mutations (6.4 months and 5.8 months, respectively; P=0.64 for interaction) (Figure 1B).

EXPOSURE TO TRIAL INTERVENTION

Figure 3.Time from Randomization to the End of the Trial Intervention.

The median number of cycles of therapy received was 12 (interquartile range, 4 to 21) in the palbociclib–fulvestrant group and 5 (interquartile range, 2 to 12) in the placebo–fulvestrant group. The Kaplan–Meier estimate of the rate of patients continuing the trial intervention at 24 months was 23% (95% CI, 19 to 28) in the palbociclib–fulvestrant group and 10% (95% CI, 6 to 15) in the placebo–fulvestrant group, and the rate at 36 months was 14% (95% CI, 11 to 18) and 5% (95% CI, 3 to 9), respectively (Figure 3). At the time of the analysis, 35 patients (10%) were continuing to receive the trial intervention in the palbociclib–fulvestrant group (median duration, 45.4 months; range, 44.2 to 51.4), as compared with 6 patients (3%) in the placebo–fulvestrant group (median duration, 44.7 months; range, 44.2 to 45.6).

DISEASE PROGRESSION AFTER TRIAL INTERVENTION

Table 1.Systemic Anticancer Therapies Received as First, Second, and Third or Greater Lines of Subsequent Treatment by More Than 10% of the Patients in Either Trial Group Who Discontinued the Intervention.

In the intention-to-treat population, 389 patients (75%) received therapy after the end of trial intervention. The median number of lines of treatment received after disease progression was 2 (range, 1 to 10) in the palbociclib–fulvestrant group and 3 (range, 1 to 10) in the placebo–fulvestrant group. The type of subsequent treatment was similar in the two trial groups, except for subsequent CDK4/6 inhibitor treatment (Table 1). Approximately 40% of the patients in each group received endocrine-based therapy as the immediate subsequent line of treatment.

Although the protocol did not allow patients to cross over to receive palbociclib, treatment with a CDK4/6 inhibitor in the subsequent or following lines of treatment after the trial intervention occurred in 4% of patients in the palbociclib–fulvestrant group and 16% of those in the placebo–fulvestrant group (Table 1). We performed a sensitivity analysis to explore the effect of this crossover on overall survival. The rank-preserving structural-failure time analysis suggested a small decrease in overall survival in the placebo–fulvestrant group after correction for the crossover effect of 27 patients (median overall survival, 27.4 months [95% CI, 23.8 to 35.4]; stratified hazard ratio for death in the palbociclib–fulvestrant group vs. the crossover-corrected placebo–fulvestrant group, 0.78 [bootstrapped 95% CI, 0.61 to 1.04]; unstratified hazard ratio, 0.77 [bootstrapped 95% CI, 0.60 to 1.00]), as compared with a median overall survival of 28.0 months before adjustment.

TIME RECEIVING SUBSEQUENT LINE OF THERAPY

In exploratory analyses, we analyzed the time from randomization to the end of the immediate subsequent line of therapy after disease progression, which was 18.8 months (95% CI, 16.4 to 20.5) in the palbociclib–fulvestrant group and 14.1 months (95% CI, 12.0 to 16.7) in the placebo–fulvestrant group (hazard ratio, 0.68; 95% CI, 0.56 to 0.84; P<0.001). The time from randomization to the first use of chemotherapy after disease progression was 17.6 months (95% CI, 15.2 to 19.7) in the palbociclib–fulvestrant group, as compared with 8.8 months (95% CI, 7.3 to 12.7) in the placebo–fulvestrant group (hazard ratio, 0.58; 95% CI, 0.47 to 0.73; P<0.001). The duration of the immediate subsequent line of therapy, according to type of treatment, was similar in the palbociclib–fulvestrant group and the placebo–fulvestrant group. Details are provided in Figures S4 and S5 in the Supplementary Appendix.

ADVERSE EVENTS

The adverse-event profile of palbociclib–fulvestrant remained consistent with that in the primary analysis (Table S1 in the Supplementary Appendix).⁷ Neutropenia of grade 3 or 4 occurred in 70% of the patients receiving palbociclib–fulvestrant and in none of the patients receiving placebo–fulvestrant, anemia of grade 3 or 4 occurred in 4% and 2% of the patients, respectively, and thrombocytopenia of grade 3 or 4 occurred in 3% and none of the patients, respectively. Febrile neutropenia remained uncommon, occurring in 1% of the patients (3 of 345 patients) who received palbociclib–fulvestrant and in none of those who received placebo–fulvestrant. Nonhematologic adverse events of grade 3 or 4 were also uncommon. Events of grade 3 or 4 that occurred at a frequency of more than 2% of the patients in the palbociclib–fulvestrant group were infections (in 5% of the patients in the palbociclib–fulvestrant group and in 3% of those in the placebo–fulvestrant group), fatigue (in 3% and 1%, respectively), and elevation in the aspartate aminotransferase level (in 3% and 2%).

Discussion

Although the results of the analysis of overall survival did not meet the prespecified threshold for statistical significance, the addition of palbociclib to fulvestrant resulted in an absolute prolongation of overall survival of 6.9 months among patients with hormone-receptor–positive, HER2-negative advanced breast cancer who had disease progression after previous endocrine therapy. This result is consistent with the significant prolongation in progression-free survival that was observed with the addition of palbociclib to fulvestrant (Fig. S6 in the Supplementary Appendix). Among patients with previous sensitivity to endocrine therapy, one of the largest subpopulations enrolled in the trial, overall survival was prolonged by 10.0 months.

Multiple studies have shown that the addition of CDK4/6 inhibitors to endocrine therapy results in substantially prolonged progression-free survival. Improvement has been observed in combination with aromatase inhibitors^6,16-18 and fulvestrant^7,19,20 for palbociclib, ribociclib, and abemaciclib therapy. A key issue has been the extent to which this benefit in progression-free survival translates to a prolongation of overall survival. In the PALOMA-3 trial, we found that the magnitude of improvement in progression-free survival (6.6 months longer with the addition of palbociclib to fulvestrant)⁹ translates directly to an improvement in overall survival of similar magnitude in the overall group of trial patients (6.9 months longer), but the difference did not reach statistical significance. This improvement was associated with a longer time from randomization to the end of the immediate subsequent line of therapy after disease progression and a longer time from randomization to the first use of chemotherapy after disease progression among patients treated with palbociclib–fulvestrant than among those who received placebo–fulvestrant. Furthermore, with this longer follow-up, a subgroup of patients who were treated with palbociclib–fulvestrant had a very long duration of disease control, with 14% of the patients continuing in the trial after 3 years of treatment with palbociclib–fulvestrant, as compared with 5% of those receiving placebo–fulvestrant.

Final data regarding overall survival from phase 3 trials of letrozole and CDK4/6 inhibitors are limited. These trials all have lower power for the statistical analysis of overall survival than for the statistical analysis of progression-free survival, and therefore the data presented in this article should be interpreted cautiously when deciding on the timing of CDK4/6 inhibitor therapy. Our data support the use of palbociclib–fulvestrant in patients with disease recurrence during endocrine therapy after at least 2 years of adjuvant therapy or in patients who received endocrine therapy alone for metastatic disease with clinical benefit. For patients for whom first-line aromatase inhibitor–based therapy is a standard of care or those who do not have a relapse while they are receiving an aromatase inhibitor, our findings do not inform the timing of palbociclib therapy.

The results regarding overall survival in the PALOMA-3 trial show the substantial challenges of finding a significant prolongation of overall survival in the context of a disease in which survival after disease progression is substantially longer than the time in the trial.²¹ To design a trial in this context that would detect a significant improvement in overall survival to result in a hazard ratio for death of 0.80 would have required a much larger trial. Accordingly, an 80% power calculation would involve more than 700 events, as compared with the approximate 46% power that results from the 310 deaths among the 521 patients who were enrolled in this trial. Future meta-analyses of CDK4/6 inhibitor studies may provide a more robust assessment of the effect of this class of drugs on overall survival, including in subgroups of patients. This trial also shows a further challenge of finding a significant benefit, because 16% of the patients in the placebo–fulvestrant group crossed over to receive a CDK4/6 inhibitor as subsequent therapy because of the commercial availability of this class of agents. Crossover to receive an investigational drug after disease progression may attenuate the observed advantage in overall survival²² and probably resulted in a modest prolongation of overall survival in the control group, thereby further reducing the power of the trial to show a significant benefit.

A planned subgroup analysis of overall survival regarding the three prespecified stratification factors identified the patients who derived the most benefit from palbociclib. In particular, patients with sensitivity to previous endocrine therapy had a substantial benefit, whereas those with intrinsic endocrine resistance had a limited benefit. This differential benefit in terms of overall survival closely mirrors the absolute prolongation of progression-free survival that was observed with palbociclib in these two populations. These data confirm that palbociclib was highly effective in augmenting responses in endocrine-sensitive cancers, but the effect may be more limited in tumors with intrinsic endocrine resistance. However, relatively few patients with intrinsic endocrine resistance were recruited in the trial, which limits the assessment of palbociclib in these patients.

Although palbociclib–fulvestrant resulted in a longer median overall survival than placebo–fulvestrant among postmenopausal patients but not among premenopausal or perimenopausal patients, this disparity can be attributed in part to the small size of the subgroup of premenopausal or perimenopausal patients and may also reflect variance in the proportion of patients with intrinsic endocrine resistance in the two subgroups. In the subgroup of premenopausal or perimenopausal patients, the percentage of patients with intrinsic endocrine resistance was higher than in the postmenopausal subgroup (30% vs. 19%).²³ Because patients with intrinsic endocrine resistance may have limited benefit from endocrine therapy in combination with palbociclib, the overall survival benefit is difficult to ascertain. Furthermore, an imbalance in certain prognostic factors between the palbociclib–fulvestrant group and the placebo–fulvestrant group in the subgroup of premenopausal or perimenopausal patients favored the control group. Premenopausal or perimenopausal patients who had been randomly assigned to the placebo–fulvestrant group had received fewer lines of previous therapy than those who had been randomly assigned to the palbociclib–fulvestrant group (lines of previous therapy, 0 or 1: 72% of the patients in the placebo–fulvestrant group vs. 58% of those in the palbociclib–fulvestrant group), and fewer patients were 40 years of age or younger (22% of patients in the placebo–fulvestrant group vs. 35% of those in the palbociclib–fulvestrant group).²³

The duration of the immediate subsequent line of therapy after disease progression after the completion of trial intervention was similar in the palbociclib–fulvestrant group and the placebo–fulvestrant group, which shows that standard treatments had similar efficacy after progression while patients were receiving palbociclib or placebo (Fig. S5 in the Supplementary Appendix). Research on the mechanisms of resistance to CDK4/6 inhibitors in the PALOMA-3 trial indicated that disease progression during palbociclib–fulvestrant treatment was due predominantly to endocrine resistance.^24,25 Analysis of circulating tumor DNA in plasma samples obtained at the end of the trial intervention revealed that the genetic profile at the end of the trial intervention was largely similar in patients treated with palbociclib and those who received placebo, with the exception of retinoblastoma (RB1) mutations that were selected in 5% of the patients who had progression during palbociclib treatment.²⁴ The data regarding overall survival in this trial suggest that the low rate of RB1 mutations selected by palbociclib has no overall detectable effect on either overall survival or sensitivity to subsequent therapies after progression during trial treatment.

Taken together, the data from the PALOMA-3 trial showed that palbociclib in combination with fulvestrant led to a 6.9-month prolongation of overall survival, although the finding did not reach significance in the intention-to-treat population. In the subgroup of patients with sensitivity to previous endocrine therapy, overall survival was 10 months longer with palbociclib–fulvestrant than with placebo–fulvestrant.

PALOMA-3: Phase III Trial of Fulvestrant With or Without Palbociclib in Premenopausal and Postmenopausal Women With Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer That Progressed on Prior Endocrine Therapy—Safety and Efficacy in Asian Patients

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Purpose

To assess efficacy and safety of palbociclib plus fulvestrant in Asians with endocrine therapy–resistant metastatic breast cancer.

Patients and Methods

The Palbociclib Ongoing Trials in the Management of Breast Cancer 3 (PALOMA-3) trial, a double-blind phase III study, included 521 patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative metastatic breast cancer with disease progression on endocrine therapy. Patient-reported outcomes (PROs) were assessed on study treatment and at the end of treatment.

Results

This preplanned subgroup analysis of the PALOMA-3 study included premenopausal and postmenopausal Asians taking palbociclib plus fulvestrant (n = 71) or placebo plus fulvestrant (n = 31). Palbociclib plus fulvestrant improved progression-free survival (PFS) compared with fulvestrant alone. Median PFS was not reached with palbociclib plus fulvestrant (95% CI, 9.2 months to not reached) but was 5.8 months with placebo plus fulvestrant (95% CI, 3.5 to 9.2 months; hazard ratio, 0.485; 95% CI, 0.270 to 0.869; P = .0065). The most common all-cause grade 3 or 4 adverse events in the palbociclib arm were neutropenia (92%) and leukopenia (29%); febrile neutropenia occurred in 4.1% of patients. Within-patient mean trough concentration comparisons across subgroups indicated similar palbociclib exposure between Asians and non-Asians. Global quality of life was maintained; no statistically significant changes from baseline were observed for patient-reported outcome scores with palbociclib plus fulvestrant.

Conclusion

This is the first report, to our knowledge, showing that palbociclib plus fulvestrant improves PFS in asian patients. Palbociclib plus fulvestrant was well tolerated in this study.

INTRODUCTION

Breast cancer mortality rates in North American and Asian countries are comparable, with one study noting that approximately 50% to 75% of Asian women have hormone receptor (HR) –positive/human epidermal growth factor receptor 2 (HER2) –negative breast cancer.^1,2 The median age of Asians at the time of breast cancer diagnosis (45 to 50 years) is lower than that of Western patients (55 to 60 years), including those in the United States.^3,4 Thus, the rate of premenopausal women with breast cancer is higher in Asian populations compared with non-Asian populations.^5,6 Cancer therapy effectiveness can also vary between Asians and non-Asians, and Asians may have a different adverse event (AE) experience versus women from other regions as a result of various reasons such as pharmacogenomics and differences in the metabolism of a specific drug.⁷

In patients with HR-positive/HER2-negative metastatic breast cancer (MBC), endocrine therapy is the mainstay of treatment⁸; however, major challenges exist when treating patients who have developed resistance to endocrine therapy with tamoxifen or aromatase inhibitors.^9,10 Thus, treatments that can overcome endocrine therapy resistance and improve outcomes are essential.

Palbociclib, an oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), prevents DNA synthesis by blocking the progression of the cell cycle from the G₁ to the S phase.^11,12 The Palbociclib Ongoing Trials in the Management of Breast Cancer 3 (PALOMA-3) study included women with HR-positive/HER2-negative advanced breast cancer whose cancer had relapsed or progressed during or after prior endocrine therapy.^13,14 In the endocrine-resistant setting, palbociclib plus fulvestrant demonstrated improved efficacy versus fulvestrant plus placebo (median progression-free survival [PFS], 9.5 v 4.6 months, respectively; hazard ratio [HR], 0.46; 95% CI, 0.36 to 0.59; P < .001).¹³ This subgroup analysis evaluates the efficacy and safety of palbociclib plus fulvestrant versus placebo plus fulvestrant in Asians and non-Asians enrolled onto PALOMA-3, a placebo-controlled clinical study.

PATIENTS AND METHODS

Patients and Study Design

PALOMA-3, an international, multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase III clinical trial, included women with HR-positive/HER2-negative advanced breast cancer whose cancer had relapsed or progressed (on the basis of histologic or cytologic confirmation of recurrent local or distant disease progression) during or within 12 months of completing adjuvant endocrine therapy or while on or within 1 month from prior endocrine therapy for advanced breast cancer or MBC.^13,14 One previous line of chemotherapy for advanced or metastatic disease was allowed. Asian patients in this analysis were defined as all patients who self-identified their race as Asian to investigators from the following options provided on the case report form: white, black, Asian, or other. Asian patients were included from eight study sites in Japan (n = 35), five sites in Korea (n = 43), and two sites in Taiwan (n = 4); 23 other Asian patients also were included in this analysis.

Patients were randomly assigned 2:1 to receive palbociclib plus fulvestrant or placebo plus fulvestrant. Patients received placebo or palbociclib 125 mg/d orally for 3 weeks followed by 1 week off; fulvestrant 500 mg was administered intramuscularly on days 1 and 15 of cycle 1 and then every 28 days (± 7 days) thereafter starting from day 1 of cycle 1.^13,14 In premenopausal patients, any luteinizing hormone–releasing hormone (LHRH) agonist was administered starting at least 4 weeks before study therapy initiation. Patients who did not receive goserelin as their LHRH agonist before study entry were switched to goserelin from the time of random assignment through the entire study treatment period. The primary objective was investigator-assessed PFS; secondary objectives included clinical benefit response (CBR), objective response rate (ORR), survival probabilities, safety and tolerability, and patient-reported outcomes (PROs). In April 2015, the independent data monitoring committee reviewed the results of the study and concluded that its primary objective had been met as the study crossed the prespecified Haybittle-Peto efficacy stopping boundary (α = .00135).¹³ The updated results of the overall population have been previously published, and these data (cutoff date: March 16, 2015) were also used in this present analysis.¹³

An institutional review board/independent ethics committee approved the protocol; the study was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent before any study procedures were started. Additional patient eligibility criteria and study design details have been described previously.^13,14

Assessments

PFS was defined as the time from the date of random assignment to the date of first documentation of objective progression of disease or death as a result of any cause in the absence of documented progression of disease, whichever occurred first. CBR was defined as the overall rate of complete response, partial response, or stable disease ≥ 24 weeks according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Objective response was defined as the overall complete response or partial response according to RECIST version 1.1. Using x-ray, computed tomography, or magnetic resonance imaging, tumor assessments were performed at baseline and every 8 weeks for the first year and then every 12 weeks. The type, incidence, severity, and seriousness of AEs and the relationship of AEs to study medications were recorded. Severity of AEs was graded on the basis of the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. A serious AE was defined as an AE that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or results in congenital anomaly or birth defect. An AE could additionally be considered serious by the investigator if it jeopardized the patient or required intervention to prevent one of the other AE outcomes.

In addition, pharmacokinetic (PK) data and PROs were assessed by race. Trough PK samples for determination of palbociclib plasma concentrations were collected from all randomly assigned patients on day 15 of cycles 1 and 2. PROs were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30, a 30-item questionnaire that includes functional scales, symptom scales, and a global health status/quality-of-life (QOL) scale.^15,16 For functional and global QOL scales, higher scores represent a better level of functioning. For symptom-oriented scales, a higher score represents more severe symptoms. PRO questionnaires were completed before dose on day 1 of cycles 1 to 4, then on day 1 of every other subsequent cycle starting with cycle 6, and finally, at the end of treatment. For PK assessments, a post hoc analysis was used for the comparison of racial subgroups.

Statistical Analyses

Study assessments of efficacy, safety, and PROs were prespecified; efficacy subgroup analyses by various baseline variables, including race, were preplanned in the protocol and statistical analysis plan. Statistical analyses by race were conducted for exploratory purposes. Demographic and baseline disease characteristics were summarized by treatment arm in a frequency table for Asians and non-Asians. Quantitative baseline variables, including age, weight, and height, were summarized using descriptive statistics (ie, median and range). Quantitative baseline variables were compared between the two treatment arms using a Wilcoxon two-sample test without adjusting for multiplicity. Efficacy analyses were performed using the intent-to-treat principle. Kaplan-Meier estimates of median PFS and the respective 95% CIs were provided for both treatment groups. PFS data between the treatment groups were compared using a log-rank test. HR was estimated from the Cox proportional hazards regression model. The odds ratio estimator and the exact test were used to compare the rates of binary efficacy end points. AEs were summarized using descriptive statistics in Asians who took one or more doses of study treatment. The within-patient averages of the palbociclib steady-state trough PK samples were summarized and compared across subgroups. PRO analyses were based on the PRO-evaluable population (ie, patients in the intent-to-treat population with a baseline assessment and one or more postbaseline assessments before the end of study treatment). Completion rates were summarized by cycle. Repeated-measures mixed-effects analyses were performed to compare on-treatment overall scores and changes from baseline between treatment groups while controlling for baseline.

RESULTS

Patients

From October 7, 2013, to August 6, 2014, 105 Asians were enrolled onto the study (74 and 31 patients in the palbociclib and placebo arms, respectively; Fig 1). Demographic and baseline disease characteristics were generally similar between Asians and non-Asians except for age, weight, and percentage of premenopausal or perimenopausal patients. Asians, compared with non-Asians, were generally younger (mean age, 53.7 v 57.7 years, respectively; P = .0013) and weighed less (mean, 56.7 v 74.6 kg, respectively; P < .001; Table 1). The percentage of premenopausal or perimenopausal women at baseline was higher in Asians (42%) compared with non-Asians (15%). Among Asians, demographic and baseline disease characteristics were generally similar between the palbociclib and placebo arms.

Fig 1 Patient disposition. (*) None of the patients discontinued treatment because of adverse events (AEs). (†) One patient (0.4%) discontinued treatment because of AEs. (‡) Two patients (1.4%) discontinued treatment because of AEs.

Table 1 Demographic and Baseline Disease Characteristics in the Asian and Non-Asian Populations Enrolled Onto the PALOMA-3 Trial

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Efficacy

The degree of PFS improvement in the palbociclib arm versus the placebo arm was similar in Asians and non-Asians (Fig 2). The median PFS in Asians was not reached in the palbociclib arm (95% CI, 9.2 months to not reached) but was 5.8 months (95% CI, 3.5 to 9.2 months) in the placebo arm (HR, 0.485; 95% CI, 0.27 to 0.87; P = .0065). In non-Asians, the median PFS was 9.5 months (95% CI, 7.6 to 11 months) in the palbociclib arm compared with 3.8 months (95% CI, 3.3 to 5.5 months) in the placebo arm (HR, 0.451; 95% CI, 0.34 to 0.59; P < .001). In Asians, the CBR was 70% (95% CI, 59% to 80%) with palbociclib plus fulvestrant and 52% (95% CI, 33% to 70%) with placebo plus fulvestrant (odds ratio, 2.216; 95% CI, 0.85 to 5.7; Table 2). In non-Asians, the CBR was 66% (95% CI, 60% to 71%) and 37% (95% CI, 29% to 46%) in the palbociclib and placebo arms, respectively (odds ratio, 3.234; 95% CI, 2.1 to 5.0; P < .001). The ORR in Asians was 19% in the palbociclib arm and 13% in the placebo arm. The sample size was underpowered to perform any statistical analysis. However, the degrees of improvement for CBR and ORR in Asians were similar to those seen in non-Asians.

Fig 2 Investigator-assessed progression-free survival (PFS) in Asian and non-Asian patients. FUL, fulvestrant; HR, hazard ratio; NR, not reached; PAL, palbociclib; PCB, placebo.

Table 2 Summary of Investigator-Assessed Best Overall Tumor Response by Treatment in Asian and Non-Asian Patients

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Safety

The exposure to study treatments was comparable between Asians and non-Asians (Table 3). Among Asians, 100% of patients in the palbociclib arm and 94% in the placebo arm experienced treatment-emergent AEs of any grade (Table 4). The most common AEs among Asians were neutropenia and leukopenia. Febrile neutropenia occurred in three Asians (4%) in the palbociclib arm, with two of these cases reported as a serious AE. On the basis of results that were unadjusted for sample size differences between Asians and non-Asians, non-Asians in the palbociclib arm generally experienced similar treatment-emergent AEs at comparable incidences (< 10%); however, in Asians, compared with non-Asians, the incidence of fatigue (19% v 44%, respectively) was lower, and the rates of neutropenia (92% v 78%, respectively), stomatitis (41% v 24%, respectively), rash (32% v 11%, respectively), and nasopharyngitis (21% v 10%, respectively) were higher (Table 4).

Table 3 Study Treatment Exposure and Duration

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Table 4 Treatment-Emergent AEs Among Asian and Non-Asian Patients (≥ 10% incidence in Asian palbociclib plus fulvestrant group)

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The median number of treatment interruptions per patient was not different between Asians and non-Asians, regardless of treatment group. The number of cycle delays per patient was higher in Asians than non-Asians, regardless of treatment group. The median relative dose was lower in Asians than non-Asians in the palbociclib group and similar between Asians and non-Asians in the placebo group (Table 3). Fourteen non-Asian patients (5.1%) in the palbociclib arm and five non-Asian patients (3.5%) in the placebo arm discontinued palbociclib or placebo treatment because of an AE.

In Asians, the overall incidence of serious AEs was 14% (10 of 73 patients) in the palbociclib arm and 23% (seven of 31 patients) in the placebo arm (Appendix Table A1). In non-Asians, the incidence of serious AEs was 13% (34 of 272 patients) and 16% (23 of 141 patients) in the palbociclib and placebo arms, respectively. In the placebo plus fulvestrant group, the incidence of serious AEs in Asians (23%) was similar to the incidence in non-Asians (16%).

PK Results

Comparison of the within-patient mean steady-state palbociclib trough concentrations in Asians and non-Asians demonstrated relative consistency in the central tendency and range of the observed values across subpopulations, indicating similar palbociclib exposure in these subpopulations (Fig 3). Geometric mean values of the within-patient mean steady-state palbociclib trough concentration values were similar for Asians and non-Asians (85.7 and 74.8 ng/mL, respectively). A population PK-pharmacodynamic (PD) analysis performed to assess the exposure-response relationship for neutropenia within PALOMA-3 showed that Asian race, baseline ALT level, and age were significant covariates on the baseline absolute neutrophil count (ANC) values. Asian race, lower baseline ALT level, and younger age were associated with lower baseline ANC values. Importantly, race was not found to be a covariate on any of the model PD response parameters. Generally, Asians in PALOMA-3 had a baseline ANC value that was 19% lower than non-Asians (Appendix Table A2).

Fig 3 Plasma palbociclib within-patient mean steady-state trough concentration in Asian and non-Asian patients. Diamonds represent the subpopulation geometric mean values, and open circles represent individual patient values. The dashed line represents the arithmetic mean value of all data from all patients. The box plot provides median and 25% and 75% quartiles with whiskers to the last point within 1.5 times the interquartile range.

PROs

Questionnaire completion rates were high at baseline and during treatment (from baseline to cycle 12, ≥ 90% of patients in each group completed all questions on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30). In Asians, no significant deterioration from baseline in global QOL was observed within the palbociclib arm. Among the Asian subgroup in the study, no significant differences between treatment arms were observed for global QOL, functioning, pain, fatigue, or nausea and vomiting (Appendix Fig A1A). Significantly greater deterioration was observed in the placebo arm versus the palbociclib arm for dyspnea (score, 1.2 v 9.2, respectively; P < .05; Appendix Fig A1B).

DISCUSSION

CDK4/6 inhibitors are now an integral part of the management of HR-positive/HER2-negative MBC.¹⁷ Palbociclib, the first-in-class CDK4/6 inhibitor approved for the treatment of HR-positive MBC, has shown impressive PFS improvement when combined with either an aromatase inhibitor¹⁸ or selective estrogen receptor downregulator¹⁴ in both patients who are endocrine sensitive and endocrine resistant. In the PALOMA-1 phase II study and PALOMA-2 phase III study of patients who had not previously received endocrine therapy, longer PFS was reported with palbociclib plus letrozole versus letrozole alone.^18,19 Similarly, in the PALOMA-3 study, in patients who had previously received endocrine therapy, palbociclib plus fulvestrant resulted in longer PFS than fulvestrant alone.¹⁴ Palbociclib has been approved in the United States and has been used in more than 48,000 patients since February 2015.²⁰ Palbociclib is also approved by regulatory authorities for advanced breast cancer in the following countries in Asia: Singapore, Malaysia, Macau, Hong Kong, and Korea. In many of these countries, palbociclib will be reviewed by health technology agencies, payers, or both. The positive clinical value of palbociclib in Asian patients should be considered alongside the economic implications.

Substantial clinical experience has been accumulated in white patients. Although few Asians were enrolled onto the PALOMA-1 study,²¹ 21% of patients in the palbociclib arm and 18% of patients in the fulvestrant arm in PALOMA-3 were Asian.¹⁴ This study adds to the limited body of literature assessing a CDK4/6 inhibitor in Asians and represents the largest patient experience with palbociclib in Asians. The present findings show that palbociclib plus fulvestrant improved PFS in Asians with HR-positive/HER2-negative MBC who experienced progression on prior endocrine therapy and that the safety profile of palbociclib plus fulvestrant in Asians was generally consistent with that observed in non-Asians. Together, these findings suggest that palbociclib is beneficial in patients who have not previously received endocrine therapy and in Asians and non-Asians who experienced relapse or progression during prior endocrine therapy.

Differences in racial background can be associated with variable efficacy outcomes and safety profiles.²² As a result of genetic variations in an enzyme responsible for doxorubicin metabolism,²³ Asians have been shown to be more susceptible to myelosuppression induced by doxorubicin compared with whites.²² In addition, a higher incidence of febrile neutropenia with docetaxel has been reported in Asians compared with whites.²² Genetic differences associated with race also can lead to differences in treatment response and efficacy. In Koreans with MBC, CYP2D6*10/*10 genetic polymorphisms have been associated with reduced plasma concentrations of the tamoxifen active metabolites endoxifen and 4-hydroxytamoxifen, as well as reduced clinical benefit (complete response, partial response, or stable disease ≥ 24 weeks) and significantly shorter median time to progression (P = .0032).²⁴ These racial variations highlight the importance of evaluating the efficacy and safety of cancer medications within the Asian population.

Similar to findings from the present analysis, the most common AEs reported in the PALOMA-1 study with palbociclib were neutropenia and leukopenia.^14,18 In the PALOMA-3 study, nonhematologic AEs were predominantly mild or moderate in severity. Moreover, an important difference of treatment exposure was observed between Asians and non-Asians in the palbociclib arm, with higher percentages of Asians experiencing dose interruptions, dose reductions, and cycle delays than non-Asians. Interestingly, the rates of grade 3 and grade 4 neutropenia were modestly higher in Asians than non-Asians. Because palbociclib exposure was similar in Asians and non-Asians, the increased rates of neutropenia cannot be explained by differential drug exposure across racial subgroups. Asian race, lower baseline ALT, and younger age were all predictors of a lower baseline ANC value. The Asians in PALOMA-3, on average, were younger and had a lower baseline ALT than the non-Asians, thus compounding effects of the covariates. Overall, in the PALOMA-3 patient population, a typical Asian patient (52 years old at enrollment with a baseline ALT of 17 U/L) had a baseline ANC value 19% lower than a typical non-Asian patient (58 years old at enrollment with a baseline ALT of 21 U/L), which may partially explain the higher rate of neutropenia observed in Asians. Importantly, race was not demonstrated to be a covariate on any of the PD response parameters, suggesting that there was no increased sensitivity to palbociclib-induced neutropenia in Asians.

MBC in premenopausal women is not well studied because clinical trials often exclude this patient population. One phase II study of 73 patients with HR-positive MBC showed that the efficacy of first-line therapy with letrozole plus goserelin in premenopausal patients was comparable with the efficacy of letrozole alone in postmenopausal patients²⁵; these findings support additional research into assessing the efficacy of other treatments in combination with goserelin in premenopausal patients with breast cancer. MBC in premenopausal women is rare in the Western world; however, higher incidences are seen in Asian countries and in developing countries such as Mexico, Latin America, and Egypt, where breast cancer is more common in younger women and is frequently diagnosed at later stages as a result of suboptimal access to health care.^3,4,26–29 Palbociclib plus fulvestrant improved PFS in both premenopausal and postmenopausal Asians in PALOMA-3. Because of the small number of patients in this cohort, no formal statistical analysis could be performed. Nevertheless, palbociclib plus fulvestrant in addition to an LHRH agonist could be a reasonable treatment option for younger patients with breast cancer who are premenopausal, including Asian patients.

Assessing PROs is important to comprehensively define the risk-benefit profile of treatments. In the current study, Asians in the palbociclib group maintained good QOL throughout the study, which is important in establishing the benefit-risk profile of combination therapy.

In conclusion, as observed in the full study population, PFS was longer in Asians with HR-positive/HER2-negative MBC who received palbociclib plus fulvestrant versus those who received placebo plus fulvestrant. Furthermore, QOL was maintained in Asians who received palbociclib. The safety profile of palbociclib was consistent with that previously reported and was similar in Asians and non-Asians. The protocol-defined dosing modification instructions for palbociclib, including adjusting dose on the basis of individual tolerability, enabled Asians to avoid discontinuation from the study as a result of an AE, allowing them to stay on treatment as long as non-Asians and thus maintain the same efficacy benefit from combination therapy. Overall, palbociclib plus fulvestrant seems to be a reasonable treatment option in Asians with HR-positive/HER2-negative MBC that has progressed on prior endocrine therapy.

Source: American Society of Clinical Oncology/JCO

Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial

Posted by zedie

Summary

Background

In the PALOMA-3 study, the combination of the CDK4 and CDK6 inhibitor palbociclib and fulvestrant was associated with significant improvements in progression-free survival compared with fulvestrant plus placebo in patients with metastatic breast cancer. Identification of patients most suitable for the addition of palbociclib to endocrine therapy after tumour recurrence is crucial for treatment optimisation in metastatic breast cancer. We aimed to confirm our earlier findings with this extended follow-up and show our results for subgroup and biomarker analyses.

Methods

In this multicentre, double-blind, randomised phase 3 study, women aged 18 years or older with hormone-receptor-positive, HER2-negative metastatic breast cancer that had progressed on previous endocrine therapy were stratified by sensitivity to previous hormonal therapy, menopausal status, and presence of visceral metastasis at 144 centres in 17 countries. Eligible patients—ie, any menopausal status, Eastern Cooperative Oncology Group performance status 0–1, measurable disease or bone disease only, and disease relapse or progression after previous endocrine therapy for advanced disease during treatment or within 12 months of completion of adjuvant therapy—were randomly assigned (2:1) via a centralised interactive web-based and voice-based randomisation system to receive oral palbociclib (125 mg daily for 3 weeks followed by a week off over 28-day cycles) plus 500 mg fulvestrant (intramuscular injection on days 1 and 15 of cycle 1; then on day 1 of subsequent 28-day cycles) or placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival. Analysis was by intention to treat. We also assessed endocrine therapy resistance by clinical parameters, quantitative hormone-receptor expression, and tumour PIK3CA mutational status in circulating DNA at baseline. This study is registered with ClinicalTrials.gov, NCT01942135.

Findings

Between Oct 7, 2013, and Aug 26, 2014, 521 patients were randomly assigned, 347 to fulvestrant plus palbociclib and 174 to fulvestrant plus placebo. Study enrolment is closed and overall survival follow-up is in progress. By March 16, 2015, 259 progression-free-survival events had occurred (145 in the fulvestrant plus palbociclib group and 114 in the fulvestrant plus placebo group); median follow-up was 8·9 months (IQR 8·7–9·2). Median progression-free survival was 9·5 months (95% CI 9·2–11·0) in the fulvestrant plus palbociclib group and 4·6 months (3·5–5·6) in the fulvestrant plus placebo group (hazard ratio 0·46, 95% CI 0·36–0·59, p<0·0001). Grade 3 or 4 adverse events occurred in 251 (73%) of 345 patients in the fulvestrant plus palbociclib group and 38 (22%) of 172 patients in the fulvestrant plus placebo group. The most common grade 3 or 4 adverse events were neutropenia (223 [65%] in the fulvestrant plus palbociclib group and one [1%] in the fulvestrant plus placebo group), anaemia (ten [3%] and three [2%]), and leucopenia (95 [28%] and two [1%]). Serious adverse events (all causalities) occurred in 44 patients (13%) of 345 in the fulvestrant plus palbociclib group and 30 (17%) of 172 patients in the fulvestrant plus placebo group. PIK3CA mutation was detected in the plasma DNA of 129 (33%) of 395 patients for whom these data were available. Neither PIK3CA status nor hormone-receptor expression level significantly affected treatment response.

Interpretation

Fulvestrant plus palbociclib was associated with significant and consistent improvement in progression-free survival compared with fulvestrant plus placebo, irrespective of the degree of endocrine resistance, hormone-receptor expression level, and PIK3CA mutational status. The combination could be considered as a therapeutic option for patients with recurrent hormone-receptor-positive, HER2-negative metastatic breast cancer that has progressed on previous endocrine therapy.

Source: Lancet Oncology

Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer

Posted by zedie

Abstract

Background

Methods

Results

Conclusions

n 2018, approximately 266,000 new cases of breast cancer are estimated to occur in women in the United States, with 41,000 deaths.¹ Of these, hormone-receptor–positive breast cancer is the most common disease subtype.² The cyclin-dependent kinases 4 and 6 (CDK4/6) are key promoters of tumor growth in hormone-receptor–positive breast cancer, cooperating with estrogen-receptor pathway activation.^3,4 Preclinical models of hormone-receptor–positive breast cancer were highly sensitive to the CDK4/6 inhibitor palbociclib (Ibrance, Pfizer),⁴ and in a subsequent phase 2 study (Palbociclib: Ongoing Trials in the Management of Breast Cancer [PALOMA]–1), palbociclib resulted in a progression-free survival benefit in patients with previously untreated, estrogen-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer.⁵ Subsequently, the randomized, phase 3 trial PALOMA-2 confirmed that palbociclib substantially prolonged progression-free survival, in combination with letrozole, as first-line therapy for estrogen-receptor–positive, HER2-negative advanced breast cancer (hazard ratio for disease progression or death, 0.58; 95% confidence interval [CI], 0.46 to 0.72).⁶

Methods

Trial Design and Patients

End Points

Oversight

Statistical Analysis

Results

Patients

Overall Survival

Figure 1. Overall Survival in the Overall Population and According to Subgroup.

The data regarding overall survival were analyzed at a cutoff date of April 13, 2018, with a median follow-up of 44.8 months and 60% data maturity (310 deaths among 521 patients). A total of 201 deaths occurred in the palbociclib–fulvestrant group, and 109 deaths in the placebo–fulvestrant group. The median overall survival was 34.9 months (95% CI, 28.8 to 40.0) in the palbociclib–fulvestrant group and 28.0 months (95% CI, 23.6 to 34.6) in the placebo–fulvestrant group. The stratified hazard ratio for death was 0.81 (95% CI, 0.64 to 1.03; P=0.09) (Figure 1A). The unstratified hazard ratio was 0.79 (95% CI, 0.63 to 1.00). The estimated rate of overall survival at 3 years in the Kaplan–Meier analysis was 50% (95% CI, 44 to 55) in the palbociclib–fulvestrant group and 41% (95% CI, 33 to 48) in the placebo–fulvestrant group.Figure 2. Overall Survival According to Patients’ Sensitivity to Previous Endocrine Therapy.

Exposure to Trial Intervention

Figure 3. Time from Randomization to the End of the Trial Intervention.

Disease Progression after Trial Intervention

Table 1. Systemic Anticancer Therapies Received as First, Second, and Third or Greater Lines of Subsequent Treatment by More Than 10% of the Patients in Either Trial Group Who Discontinued the Intervention.

Time Receiving Subsequent Line of Therapy

Adverse Events

Discussion

Source: NEJM

A Review of Fulvestrant in Breast Cancer

Posted by zedie

Abstract

Fulvestrant is a selective estrogen receptor degrader that binds, blocks and degrades the estrogen receptor (ER), leading to complete inhibition of estrogen signaling through the ER. This review article further explains the mechanism of action of the drug and goes on to review the trials carried out to optimize its dosing. Multiple trials have been undertaken to compare fulvestrant with other endocrine treatments, and results have shown it to have similar efficacy to anastrozole, tamoxifen and exemestane at 250 mg every 28 days. However, when given at 500 mg every 28 days, with an extra loading dose on day 14, it has demonstrated an improved progression-free survival (PFS) compared to anastrozole. We look at how fulvestrant has been used in combination with CDK4/6 inhibitors such as palbociclib (PALOMA-3) and ribociclib (MONALEESA-3) and drugs targeting the PI3K/AKT/mTOR pathway such as pictilisib (FERGI) and buparlisib (BELLE-2 and BELLE-3). We then go on to describe a selection of the ongoing clinical trials looking at combination therapy involving fulvestrant. Finally, we review the effect of fulvestrant in patients who have developed resistance to aromatase inhibitors via ESR1 mutation, where it has been shown to offer a PFS benefit that is further improved by the addition of the CDK4/6 inhibitor palbociclib. Whilst fulvestrant is clearly an effective drug as monotherapy, we believe that its role in the treatment of ER-positive breast cancer may be best reserved for combination therapy, and whilst there are multiple trials currently in progress, it would appear that the combination with CDK4/6 inhibitors would offer the greatest promise in terms of balancing benefit with toxicity.

Introduction

Breast cancer has the highest incidence of any cancer in the world, with 1.7 million new cases recorded in 2012, accounting for 12% of all new cancer diagnoses. It is also the fifth highest cause of cancer death, with 521,827 deaths worldwide in 2012 (Cancer Research UK).

Approximately 80% of breast cancers express the estrogen receptor (ER), with their survival and proliferation driven by estrogen acting as the ligand and binding to the estrogen receptor, which is then translocated to the cancer cell nucleus. This in turn initiates a signaling cascade, resulting in the propagation of breast cancer cells. The ER is a nuclear receptor. Transcriptional activity is regulated by two activating functional domains: AF1 and AF2. The former, located in the N-terminal domain, acts independently of estrogen, becoming activated through phosphorylation. The latter, however, located in the ligand-binding domain, requires the presence of estrogen for activation [1].

This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

Mechanism of Action

Tamoxifen and fulvestrant are both anti-estrogens that counteract the effects of estrogen by binding directly to the ER, thereby working as an antagonist. Tamoxifen is a selective estrogen receptor modulator (SERM) that blocks E2-mediated activity of AF2, resulting in ER-antagonistic activity, although partial agonistic activity remains. Unlike tamoxifen, fulvestrant-induced conformational change of the ER disrupts both AF2- and AF1-related transcriptional activity [1].

Furthermore, the complex formed when fulvestrant binds to the ER is unstable, resulting in its accelerated degradation. Fulvestrant therefore acts as both a competitive antagonist and a selective estrogen receptor degrader (SERD), causing a reduction in cellular ER alpha levels [2]. In addition, it acts almost exclusively as an ER antagonist, whereas tamoxifen is also a partial agonist of ER [3] (Fig. 1).

Fulvestrant has a relatively high binding affinity to the ER, which is 89% that of estradiol [4]. It also impairs dimerization of the receptor, thereby blocking its nuclear localization [5], and the unstable complex formed results in accelerated degradation of the ER protein [6]. Thus, fulvestrant binds, blocks and degrades the ER, leading to complete inhibition of estrogen signaling through the ER [7].

Early Trials

One of the limiting factors in the dosing of fulvestrant is the practicality of administration. Fulvestrant has poor solubility and must be administered via intramuscular injection, thereby limiting the volume and dose that can be delivered. The initial dose, as used in the trials explained here, was defined as 250 mg every 28 days, and this dose was tested in a range of randomized phase III trials comparing fulvestrant with other, standard-of-care endocrine therapies in the first-line or subsequent settings.

Two parallel studies in patients progressing after prior endocrine treatment showed that fulvestrant at a dose of 250 mg every 4 weeks was as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment [8, 9]. In both trials, the median time to progression (TTP) for fulvestrant and anastrozole was comparable: 5.5 months versus 5.1 months (HR 0.98; 95% CI 0.8–1.21; p = 0.84) and 5.4 versus 3.4 months (HR 0.92; 95% CI 0.74–1.14; p = 0.43), respectively [8, 9]. A prospectively planned, combined analysis of the two studies also showed comparable outcome (HR 0.96; 95% CI 0.83–1.11; p = 0.61). In each of the studies, both drugs were well tolerated [10]. There was also no significant difference in the secondary endpoint of objective response rate (ORR), with 19.2% responding in the fulvestrant arm and 16.5% in the anastrozole arm (p = 0.31).

Another trial went on to compare fulvestrant with tamoxifen in patients who had not received prior endocrine therapy for metastatic disease and had not received adjuvant endocrine therapy within 12 months. Again, this trial showed no significant difference in the primary endpoint between the two investigatory arms, with a median TTP of 6.8 months for fulvestrant and 8.3 months for tamoxifen (HR 1.18; 95% CI 0.98–1.44; p = 0.088) [11]. The secondary endpoint, ORR, was also comparable between arms (OR 0.87; 95% CI 0.61–1.24; p = 0.45). However, exploratory survival analysis suggested a benefit for tamoxifen over fulvestrant (HR 1.29; 95% CI 1.01–1.64; p = 0.04) [11].

Finally, two randomized trials compared fulvestrant at the dose of 250 mg every 4 weeks to the steroidal aromatase inhibitor exemestane as single-agent therapy or in combination with the non-steroidal aromatase inhibitor anastrozole. In the EFECT study, there was no difference in TTP between fulvestrant and exemestane, with a median TTP of 3.7 months observed in both arms (HR 0.96; 95% CI 0.82–1.13; p = 0.65) [12]. Interestingly, this study used a loading dose regimen for fulvestrant, with 500 mg given on day 0, and then 250 mg given on days 14 and 28, before repeating every 28 days. The different regimens for fulvestrant administration will be discussed later in this review.

The SoFEA phase III study investigated fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal advanced cancer patients [13]. Again, the loading regimen previously described was used for the administration of fulvestrant. Once more, there was no significant difference among the three arms, with median progression-free survival (PFS) of 4.4, 4.8 and 3.4 months, respectively, for the three arms, demonstrating that double endocrine treatment is no more effective than fulvestrant alone or exemestane.

What is the Optimal Dose of Fulvestrant?

Originally, fulvestrant was prescribed as 250 mg every 28 days, and other than the EFECT study, the previously described randomized trials comparing fulvestrant to both steroidal and non-steroidal aromatase inhibitors and tamoxifen were carried out using this dosing scheme. However, there has been much debate about the best dose and optimal dosing schedule for fulvestrant, and several trials have sought to address this issue. These include neoadjuvant window-of-opportunity trials looking at the effect of fulvestrant therapy on biomarkers, as well as phase II and III clinical trials in the advanced breast cancer setting.

In a biomarker-driven preoperative window trial (NEWEST), researchers investigated the dose effect of fulvestrant on a range of biomarkers. The study included postmenopausal women with newly diagnosed ER-positive breast cancer. Women were given either 500 mg per month plus 500 mg on day 14 of month 1 or 250 mg per month as preoperative therapy. The primary endpoint for this study was the change in the Ki-67 labeling index from baseline to week 4. The study showed that the higher dose and intensified loading schedule was associated with significantly increased down-regulation of Ki-67 (−78.4% vs. −47.4%; p < 0.0001) [14].

In addition, the higher dose of fulvestrant was also associated with increased down-regulation of ER, with ER expression reduced by 25% with the 500-mg dose compared to a 13.5% reduction with the 250-mg dose. Changes in Ki-67 and ER expression were both measured at day 28. This demonstrates that fulvestrant is able to work more potently as an ER degrader with this dose scheduling. Importantly, these data show that not only does the increased dose have a greater effect on down-regulating cancer cell proliferation, but it also has a direct effect on the ER itself.

The synchronous FINDER 1 and FINDER 2 studies were designed to investigate the importance of different dosing schedules in relation to the efficacy and tolerability of fulvestrant in Japanese and Western populations, respectively [15, 16]. The approved dose (AD) of 250 mg/month, a loading dose (LD) of 500 mg on day 0, followed by 250-mg doses on days 14 and 28 and monthly thereafter, and a high dose (HD) of 500 mg on days 0, 14 and 28 and then monthly thereafter, were explored. Neither study found a statistically significant difference among the three doses, using overall response rate (ORR) as their primary outcomes, but these phase II studies were ultimately underpowered to demonstrate moderate differences.

FINDER 1 found no significant difference among the three groups, with ORR of 11.1%, 17.6% and 10.6%, respectively [15]. FINDER 2 found a trend towards greater efficacy with the higher dose, but again, no significant difference was found among the three groups, with ORR of 8.5%, 5.9% and 15.2%, respectively [16]. Both trials were small, with 143 and 144 patients, respectively, and were essentially underpowered to demonstrate clinically small or moderate differences. In addition, both trials used ORR as the primary endpoint, which is considered suboptimal for comparing endocrine therapies. Tolerability, however, was similar throughout all arms within both studies.

The relevance of dose and schedule was further assessed in the CONFIRM trial, which included 736 postmenopausal patients (more than the two FINDER trials combined) who had already experienced progression on prior endocrine treatment. This phase III trial compared fulvestrant 250 mg/month with fulvestrant 500 mg/month with accelerated loading. The primary endpoint was PFS, with OS a secondary endpoint. Fulvestrant 500 mg was associated with a statistically significant increase in PFS compared to fulvestrant 250 mg (HR 0.80; 95% CI 0.68–0.94; p = 0.006), though interestingly, objective response rates were similar between the two arms (9.1% vs. 10.2%, respectively) [17]. Moreover, OS was also significantly better in the fulvestrant 500-mg arm, with a median OS of 26.4 months compared to 22.3 months in the 250-mg arm (HR 0.81; 95% CI 0.69–0.96; p = 0.02) [18]. Both dosing regimens were well tolerated.

Taken together, these data show that the higher dose of fulvestrant provides a statistically significant improvement in both PFS and OS, without an increase in toxicity, and so the higher dose has been adopted as the standard. Fulvestrant 500 mg/month with a loading dose is now the recommended dose.

Comparison Trials with Fulvestrant 500 mg

Having established an improved standard dose for fulvestrant, it has since been compared once more to aromatase inhibitors to see whether this improvement in PFS and OS compared to the lower dose could be translated into an improvement over to the established aromatase inhibitors, as opposed to the equivalence that was shown previously when the suboptimal fulvestrant dose of 250 mg was used.

The FIRST study was a phase II study of 205 patients, investigating the activity of fulvestrant 500 mg versus anastrozole 1 mg in patients without previous exposure to endocrine therapy in the advanced breast cancer setting. The primary endpoint was clinical benefit rate (CBR), defined as the proportion of patients experiencing an objective response or stable disease for 24 weeks or longer. CBR was similar for fulvestrant and anastrozole (72.5% vs. 67%, respectively), as was ORR (36% vs. 35.5%). However, TTP was significantly greater for fulvestrant at both the initial analysis [19] and the pre-planned follow-up analysis, with TTP at the latter time point of 23.4 months for fulvestrant and 13.1 months for anastrozole (HR 0.66; 95% CI 0.47–0.92; p = 0.01) [20]. Moreover, when (albeit unplanned) overall survival analysis was performed, it showed an OS of 54.1 months for fulvestrant and 48.4 months for anastrozole, an increase of 5.7 months (HR 0.70; 95% CI 0.5–0.98; p = 0.04) [21]. Once again, there was similar tolerance between the two drugs.

These findings were the basis for the FALCON phase III trial that included 462 postmenopausal women who had not previously received any form of endocrine therapy (adjuvant or metastatic). This trial was designed to confirm the efficacy of fulvestrant 500 mg compared to an aromatase inhibitor, anastrozole. A statistically significant improvement in the primary endpoint, PFS, was observed with fulvestrant relative to anastrozole (16.6 months in the fulvestrant arm vs. 13.8 months with anastrozole [HR = 0.797; 95% CI 0.637–0.999; p = 0.0486]), with similar adverse event rates [22].

Subgroup analysis suggested that patients without visceral disease might benefit most from receiving fulvestrant. PFS in this subgroup increased from 13.8 months in patients treated with anastrozole to 22.3 months for fulvestrant-treated patients (HR 0.59; 95% CI 0.42–0.84). This compares to similar efficacy in patients with visceral disease, with a PFS of 15.9 months for anastrozole and 13.8 months for fulvestrant (HR = 0.99). At the time of writing, the OS data are immature but have so far revealed no difference between the drugs [22]. At data cutoff, 67 (29%) of 230 patients in the fulvestrant group and 75 (32%) of 232 patients in the anastrozole group had died (HR 0.88, 95% CI 0.63–1.22, p = 0.4277).

Fulvestrant-Based Combination Therapy

Fulvestrant has been evaluated in various combinations, either with other endocrine agents or with novel targeted agents. Three studies have explored endocrine/endocrine combinations [23, 13, 24], with conflicting results. The SoFEA and FACT trials showed no benefit [23, 13], whereas the SWOG S0226 trial showed a slightly improved PFS of 15 months with the combination compared to 13.5 months with anastrozole alone (HR 0.8; 95% CI 0.68–0.94; p = 0.007) [24]. However, all of these studies used a suboptimal dosing regimen for fulvestrant, with 500 mg on day 1 but only 250 mg on day 15, and monthly from day 29 onwards. Moreover, the SWOG S0226 trial lacked a fulvestrant monotherapy arm.

Fulvestrant has since been combined with several different classes of targeted agents, namely CDK4/6 inhibitors, drugs targeting the PI3K/AKT/mTOR pathway and histone deacetylase (HDAC) inhibitors.

Cyclin-dependent kinases (CDKs) promote cell-cycle progression, with CDK4/6 playing a pivotal role in ER-positive breast cancer, regulating the G1-to-S-phase of the cell cycle. [25]. Several CDK4/6 inhibitors are now approved or currently in clinical development, including palbociclib, ribociclib and abemaciclib. Both palbociclib and ribociclib have been shown to substantially increase PFS in combination with the aromatase inhibitor letrozole in patients without prior endocrine treatment for metastatic breast cancer (PALOMA-2 study [26]; MONALEESA-2 study [27].

The PALOMA-3 study investigated fulvestrant with palbociclib or placebo in both pre- and postmenopausal patients who had progressed on previous endocrine treatment. The trial demonstrated a substantial increase in PFS, from 4.6 months in the placebo arm to 9.5 months in the palbociclib arm (HR = 0.46; 95% CI 0.36–0.59; p < 0.0001). In addition, ORR increased from 10.9% in patients receiving fulvestrant alone to 24.6% in those receiving the combination. Although the incidence of grade 3–4 adverse events increased from 22% to 73%, most of these events were uncomplicated myelosuppression (in particular neutropenia) and did not significantly affect patients’ quality of life. The risk of infection was low compared to chemotherapy across all studies with CDK4/6 inhibitors, affecting approximately 1% of patients. Interestingly, the added benefit of CDK4/6 inhibitors was seen irrespective of the degree of endocrine resistance, hormone receptor expression level or PIK3CA mutational status [28].

Other trials investigating the value of the CDK4/6 inhibitors are ongoing. The FLIPPER trial is a phase II study comparing fulvestrant and palbociclib with fulvestrant and placebo in the first-line metastatic setting. PARSIFAL is a phase II trial investigating the best endocrine therapy in combination with palbociclib, randomizing first-line patients to fulvestrant or letrozole. The MONALEESA-3 is a randomized placebo-controlled phase III study investigating the addition of ribociclib to fulvestrant. Finally, MONARCH 2 is also a randomized, placebo-controlled phase III study, but is investigating abemaciclib in combination with fulvestrant.

A second main target for combination endocrine therapy is the PI3K/AKT/mTOR pathway. Activation of the PI3K pathway has been shown to play a major role in promoting resistance to endocrine therapy [29]. This can be driven by either mutations in or up-regulation of the PIK3CA gene. Combination therapy with the mTOR inhibitor everolimus plus exemestane in the BOLERO-2 study demonstrated a significant benefit in PFS, but also showed substantially increased toxicity with the combination therapy. Trials with PI3K inhibitors were begun in the hope of improving on these results. Many of these studies used fulvestrant as the endocrine backbone. The efficacy of two different pan-PI3K inhibitors, pictilisib and buparlisib, has been assessed in combination with fulvestrant in three placebo-controlled randomized clinical trials: the phase II FERGI trial investigating pictilisib [30] and the phase III BELLE-2 and BELLE-3 trials investigating buparlisib (SABCS 2016).

The FERGI trial investigated the activity of the pan-PI3K inhibitor pictilisib in combination with fulvestrant in two parts. The first part included all patients with endocrine-resistant advanced breast cancer. The second part included only patients harbouring PI3K mutations. No significant PFS was seen in either stage of the study, with PFS of 6.6 months for pictilisib and 5.1 months for placebo in part 1 (HR = 0.74; 95% CI 0.52–1.06; p = 0.096) and PFS of 5.4 and 10 months, respectively, in part two (HR = 1.07; 95% CI 0.53–2.18; p = 0.84) [30]. There was also greater toxicity seen with pictilisib, potentially preventing it from being dosed sufficiently to provide efficacy. The investigators felt that a more specific inhibitor might allow more efficacious dosing.

BELLE-2 assessed the more pan-PI3K inhibitor buparlisib. The trial included women with hormone-resistant advanced breast cancer, stratified by the presence of PIK3CA mutations, as detected either in tumor tissue or from circulating tumor DNA (ctDNA). In the full study population, a small but significant increase in PFS from 5 to 6.9 months was seen with the addition of buparlisib to fulvestrant (HR = 0.78; p < 0.001). Interestingly, in the patients with a PIK3CA mutation, the relative benefit was larger, with an increase in median PFS from 3.2 to 7 months (HR = 0.56; p < 0.001). This was, however, associated with an increase in serious adverse effects seen with PI3K inhibition, including hyperglycaemia, hepatotoxicity and depression.

Also interestingly, no difference was seen in PFS between the full population and the PIK3CA-mutant patients in the arms receiving buparlisib, with the improved effect seemingly due to the fact that the PIK3CA-mutant patients progressed more rapidly than the full population when using fulvestrant monotherapy. This could imply that the presence of a PIK3CA mutation is an independent poor prognostic marker for single-agent endocrine therapy.

The BELLE-3 study is another phase III placebo-controlled study of the combination of buparlisib and fulvestrant for patients who had progressed on or within 30 days of endocrine and mTOR inhibitor therapy given as the last therapy before study entry, and no more than one prior chemotherapy regimen for advanced disease The rationale was that mTOR1 inhibition elicits AKT phosphorylation via feedback activation. PI3K inhibitors then abrogate AKT phosphorylation elicited by mTORC1 inhibition [31, 32]. The primary endpoint of PFS was met with a PFS of 3.9 months in the buparlisib arm compared to 1.8 months in the placebo arm (HR 0.67; 95% CI 0.53–0.84; p < 0.001). Response rates were also greater with ORR in the buparlisib arm 7.6% compared to 2.1% in the placebo arm. There was, however, an increase in toxicity in the combination arm with grade 3/4 adverse events almost twice as frequent (62% vs. 34%). These were notably in the form of raised transaminases and mood disorders. This may represent a significant challenge to safely delivering this combination (Di Leo et al. [33]).

One of the main limitations of Pi3K inhibitors is tolerability, especially of pan-PI3K inhibitors; thus newer, more specific agents are being developed. Trials are under way to further explore the combination of fulvestrant with drugs targeting the PI3K/AKT/mTOR pathway. MANTA is a phase II study exploring its use in combination with two different mTOR inhibitors: everolimus, which is already licensed in combination with exemestane; and vistusertib, a novel mTOR inhibitor. Taselisib is selective for the PI3Kα isoform, and so the hope is that it will be less toxic than the previously described PI3K inhibitors, allowing more potent dosing. SANDPIPER is an ongoing study investigating the use of fulvestrant alongside taselisib in a placebo-controlled phase III trial. Similarly, the SOLAR-1 study is a phase III double-blind placebo-controlled study of another selective PI3K inhibitor, alpelisib, in combination with fulvestrant in two different cohorts, the first having PIK3CA mutations and the second a PIK3CA wild-type cohort.

ESR1 Mutations and Fulvestrant

There is increasing evidence implicating ESR1 mutations as an important driver of acquired resistance to endocrine treatment [34]. ESR1 mutations are rare in primary breast cancer but are more prevalent in metastatic cancers, especially in patients previously treated with aromatase inhibitors, implying that these mutations are acquired [35, 36, 37]. These mutations result in the ER becoming constitutively active, and have therefore been associated with resistance to aromatase inhibitors and tamoxifen [35, 36].

Fulvestrant is a selective estrogen receptor degrader. Thus it is potentially able to degrade the ER and consequently to stop the up-regulation of downstream proliferation even once it becomes constitutively active. This is supported by data from further analysis of tissue from the SoFEA trial showing that patients with ESR1 mutations had an improved PFS of 5.7 months with fulvestrant compared to 2.6 months with exemestane (HR = 0.52; 95% CI 0.30–0.92; p = 0.02) [38].

Spoerke et al. investigated hotspot mutations in ESR1 and PIK3CA in ctDNA from participants of the aforementioned FERGI trial. ESR1 mutations were observed in over a third of patients and were enriched in those with luminal A (41.4%) and PIK3CA-mutated (44.4%) tumors. It seems intuitive that luminal A cancers should have a greater frequency of ESR1 mutations, as they are likely to have been exposed to several lines of aromatase inhibitors over a longer time course than other breast cancer subtypes [39]. Despite the fact that the FERGI trial was a negative study, a post hoc analysis of patients with ESR1 mutations suggested an improvement in PFS from 3.7 months with placebo to 7.2 months with PI3K inhibition, suggesting that the PI3K/AKT/mTOR pathway is associated with resistance through ESR1 mutation [39].

Spoerke’s further tissue and ctDNA analysis of the FERGI trial provides no evidence that PFS with fulvestrant treatment is any different for patients with ESR1 mutations than for those with wild-type ESR1. This suggests that these mutations might not be associated with innate or acquired resistance to fulvestrant.

Fribbens et al. analysed samples taken from patients in the SoFEA and PALOMA-3 studies and analysed the impact of ESR1 mutations. In SoFEA, patients with ESR1 mutations had improved PFS with fulvestrant compared to exemestane (HR = 0.52), whereas those with wild-type ESR1 had similar PFS (HR = 1.07) [38]. In PALOMA-3, fulvestrant plus palbociclib improved PFS compared to fulvestrant plus placebo in both ESR1-mutant (HR = 0.43) and wild-type (HR = 0.49) patients [38].

Conclusions

Fulvestrant is an important endocrine therapy that has demonstrated substantial clinical benefit in many phase 3 trials, either alone or in combination with other agents. The trials involving fulvestrant are listed in Table 1. The majority of trials to date have explored its use in the metastatic setting, whereas there are limited data available for early breast cancer, partly because the requirement of intramuscular injection was considered less favorable in the adjuvant setting. Indeed, fulvestrant is not licensed for use in this setting. However, the development of oral SERDs might be able overcome this limitation, provided they can demonstrate improved efficacy over current treatment options. It will also be interesting to see whether oral availability will allow higher doses to be achieved, thereby potentially further increasing activity.Table 1 Summary of key trials involving fulvestrant

Full size table

The FALCON study suggests that fulvestrant is the most active single-agent endocrine therapy for postmenopausal women in the metastatic setting. It is clear that in terms of dosing and schedule, the higher dose of 500 mg on days 0, 14 and 28, and then every 28 days appears to be the most efficacious way to give the drug, balancing effectiveness and tolerability, as shown in the CONFIRM study. The remaining question is whether it is best used in monotherapy or in combination with other drugs. Combinations of fulvestrant and other endocrine treatments have not shown a clear advantage over single-agent therapy. However, fulvestrant might offer some advantages compared to other endocrine treatments as an endocrine backbone of combination therapy, most notably the ability to overcome ESR1 mutations that might be seen in patients who have relapsed on or after adjuvant aromatase inhibitors.

At present, most of the available evidence for the combination of fulvestrant and targeted biological therapies is for the CDK4/6 inhibitor palbociclib and PI3K inhibitors. The CDK4/6 inhibitors may offer the most promise, as the currently available PI3K inhibitors are associated with side effect profiles that limit their dosing to an extent that compromises their effectiveness. However, this is clearly an area of significant ongoing research, and additional combinations will hopefully be revealed over the coming years.

A Review of Fulvestrant in Breast Cancer

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Abstract

Introduction

Material and methods

Studied variables

Statistical analysis

Ethics approval

Consent to participate

Results

Study population

Effectiveness outcomes

Safety profile

Discussion

Conclusion

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Abstract

BACKGROUND

METHODS

RESULTS

CONCLUSIONS

Methods

TRIAL DESIGN AND PATIENTS

END POINTS

OVERSIGHT

STATISTICAL ANALYSIS

Results

PATIENTS

OVERALL SURVIVAL

EXPOSURE TO TRIAL INTERVENTION

DISEASE PROGRESSION AFTER TRIAL INTERVENTION

TIME RECEIVING SUBSEQUENT LINE OF THERAPY

ADVERSE EVENTS

Discussion

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Summary

Background

Methods

Findings

Interpretation

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Abstract

Background

Methods

Results

Conclusions

Methods

Trial Design and Patients

End Points

Oversight

Statistical Analysis

Results

Patients

Overall Survival

Exposure to Trial Intervention

Disease Progression after Trial Intervention

Time Receiving Subsequent Line of Therapy

Adverse Events

Discussion

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Abstract

Introduction

Mechanism of Action

Early Trials

What is the Optimal Dose of Fulvestrant?

Comparison Trials with Fulvestrant 500 mg

Fulvestrant-Based Combination Therapy

ESR1 Mutations and Fulvestrant

Conclusions

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