Fulvestrant in postmenopausal women with locally advanced or metastatic breast cancer that has progressed on prior endocrine therapy: a guide
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Fulvestrant
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Abstract Although the aromatase inhibitor anastrozole has been shown to be very effective in the treatment of hormone-dependent postmenopausal breast cancer, some patients with advanced disease will develop resistance to treatment. To investigate therapeutic strategies to overcome resistance to anastrozole treatment, we have used an intratumoral aromatase model that simulates postmenopausal breast cancer patients with estrogen-dependent tumors. Growth of the tumors in the mice was inhibited by both anastrozole and fulvestrant compared with the control tumors. Nevertheless, tumors had doubled in size at 5 weeks of treatment. We therefore investigated whether switching the original treatments to anastrozole or fulvestrant alone or the combination of anastrozole plus fulvestrant would reduce tumor growth. The results showed that the best strategy to reverse the insensitivity to anastrozole or fulvestrant is to combine the two agents. Additionally, the tumors treated with anastrozole plus fulvestrant from the beginning had only just doubled their size after 14 weeks of treatment, whereas the anastrozole and fulvestrant treatments alone resulted in 9- and 12-fold increases in tumor size, respectively, in the same time period. Anastrozole plus fulvestrant from the beginning or in sequence was associated with down-regulation of signaling proteins involved in the development of hormonal resistance such as insulin-like growth factor type I receptor β, mitogen-activated protein kinase (MAPK), p-MAPK, AKT, mammalian target of rapamycin (mTOR), p-mTOR, and estrogen receptor α compared with tumors treated with anastrozole or fulvestrant alone. These results suggest that blocking the estrogen receptor and aromatase may delay or reverse the development of resistance to aromatase inhibitors in advanced breast cancer patients. [Cancer Res 2008;68(9):3516–22]
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Fulvestrant shows dose-dependent biological activity. Greater estrogen-receptor (ER) blockade may feasibly be achieved by combining fulvestrant with anastrozole. This pre-surgical study compared fulvestrant plus anastrozole versus either agent alone in patients with ER-positive breast cancer.
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Abstract Background: Fulvestrant 250 mg has been shown to be at least as effective as anastrozole as second-line endocrine therapy for advanced hormone receptor-positive (HR+) breast cancer. However, there are biological and clinical data suggesting that fulvestrant 500 mg is more effective than 250 mg. The Fulvestrant First-Line Study Comparing Endocrine Treatments (FIRST) was designed to compare fulvestrant 500 mg with anastrozole in the first-line setting. The primary analysis reported that fulvestrant 500 mg was at least as effective as anastrozole in terms of clinical benefit rate and objective response rate. At data cut-off for the primary analysis, performed 6 months after the last patient (pt) was randomized, 117 (57.1%) pts were receiving study treatment, and median time to progression (TTP) was not reached for fulvestrant 500 mg vs 12.5 months for anastrozole (HR 0.63; 95% CI 0.39, 1.00; p=0.0496). Here, we report a follow-up data analysis of TTP and time to treatment failure (TTF). Methods: This was a Phase II, randomized, open-label, multicenter study comparing fulvestrant 500 mg (500 mg i.m. on Day 0, then 500 mg i.m. on Days 14 and 28 and every 28 days thereafter) with anastrozole (1 mg/day p.o.) as first-line treatment for postmenopausal women with advanced breast cancer. Follow-up analysis was performed when 79.5% of pts had discontinued study treatment. TTP was defined by RECIST before data cut-off for the primary analysis, and investigator opinion after data cut-off. TTF was defined as time from randomization to cessation of trial therapy. In the fulvestrant 500 mg group, TTF was derived as last injection plus 14 days, representing the midpoint in the window where treatment was withdrawn. Best overall response to first subsequent breast cancer therapy, WHO-PS, and serious AEs are also reported. Results: A total of 205 pts received fulvestrant 500 mg (n=102) or anastrozole (n=103). At this follow-up analysis with data cut-off March 26 2010, median follow-up for TTP across both treatment groups was 16.5 months. Median TTP was 23.4 months for the fulvestrant 500 mg group vs 13.1 months for the anastrozole group, corresponding to a 35% reduction in risk of progression (HR 0.66; 95% CI 0.47, 0.92; p=0.01). Median TTF was 17.6 months vs 12.7 months for the fulvestrant 500 mg and anastrozole groups, respectively (HR 0.73; 95% CI 0.54, 1.00; p=0.05). The best overall response to subsequent therapy was similar between the treatment groups (including 15 pts [23.8%] in the fulvestrant 500 mg group and 15 pts [21.1%] in the anastrozole group with either a complete or partial response) and there were no clinically important differences in terms of WHO-PS. Fulvestrant 500 mg was well tolerated and no new safety concerns were documented. Conclusion: With significantly longer follow-up, the TTP and TTF results from this analysis are consistent with the analysis of TTP at the primary data cut-off. Taken together, these results suggest an efficacy benefit for fulvestrant 500 mg compared with anastrozole as first line endocrine therapy for pts with HR+ advanced breast cancer. These data provide further support that if fulvestrant is used in advanced breast cancer then the preferred dose should be 500 mg. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S1-3.
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Abstract Background: Anastrozole depletes estrogen via aromatase inhibition and fulvestrant binds and degrades estrogen receptor. In a Phase III trial we compared the concurrent use of these agents to anastrozole alone or sequential anastrozole and fulvestrant in first-line therapy of hormone receptor-positive metastatic breast cancer in postmenopausal women, and demonstrated improved progression-free (PFS) and overall survival (OS)-NEJM 2012. Now we report PFS and OS five years after the initial positive findings. Methods: A total of 707 patients were randomized to either 1 mg anastrozole P.O. daily (Arm 1) or to the combination of anastrozole and fulvestrant (Arm 2). Fulvestrant was administered as a loading dose of 500 mg on day 1, 250 mg on days 14, 28 and monthly thereafter. Randomization was stratified by adjuvant tamoxifen use. The primary endpoint was PFS with OS a secondary outcome. 40% patients not in visceral crisis crossed over to fulvestrant after progression on arm 1. Analysis of survival was by 2-sided stratified log-rank tests and Cox regression using intent-to-treat. Subset analyses include treatment effect by adjuvant tamoxifen exposure, initial sites of metastases and time from diagnosis. Results: There were 646 PFS events (328 and 318 for arms 1 and 2, respectively) among 694 eligible patients (345 and 349, respectively). Overall, median PFS was 13.5 months for arm 1 and 15.0 months for the arm 2 (log-rank p=0.007; HR=0.81 (95% CI 0.69-0.94)). This benefit extended similarly in visceral and non-visceral subgroups. In subset analysis for Arms 1 and 2, respectively, in tamoxifen-naive women (60%, n=414), median PFS was 12.7 vs. 16.7 months (log-rank p=0.002; HR=0.73 (95% CI 0.60-0.89) while in women exposed to tamoxifen, median PFS was 13.9 vs. 13.6 months (log-rank p=0.57; HR=0.93 (95% CI 0.73-1.19)). An improved OS in the combination arm was seen, median OS 42 and 50 months in arms 1 and 2, based on 261 and 247 deaths, respectively (log-rank p=0.028; HR=0.82 (95% CI 0.69-0.98)). In subset analysis in tamoxifen-naive women, median OS was 40.3 vs. 52.2 months for Arms 1 and 2, respectively (log-rank p=0.007; HR=0.73 (95% CI 0.58-0.92)) while in women exposed to tamoxifen, median OS was 43.5 vs. 48.2 months (log-rank p=0.85; HR=0.97 (95% CI 0.74-1.27). Patients with initial diagnosis >10 years benefitted most from the combination (HR=0.66 (95% CI 0.49-0.89)) regardless of tamoxifen exposure. Patients in Arm 1 who crossed over had post-progression survival similar to post-progression survival of Arm 2 patients. Conclusion: The addition of fulvestrant to anastrozole was associated with improved long-term PFS and OS compared to anastrozole alone, despite the use of fulvestrant at a dose lower than the approved, and despite the substantial cross over to fulvestrant after progression on anastrozole alone. The benefit was especially notable in those without recent exposure to adjuvant endocrine therapy. Ongoing translational medicine studies will further refine the need for up front fulvestrant. ClinicalTrials.gov:NCT00075764. Funding: NIH/NCI U10CA180888, U10CA180819 and AstraZeneca. Citation Format: Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NL, Lew DL, Hayes DF, Gralow JR, Linden HM, Livingston RB, Hortobagyi GN. A phase III randomized trial of anastrozole and fulvestrant versus anastrozole or sequential anastrozole and fulvestrant as first-line therapy for postmenopausal women with metastatic breast cancer: Final survival outcomes of SWOG S0226 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD5-07.
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We previously reported prolonged progression-free survival and marginally prolonged overall survival among postmenopausal patients with hormone receptor–positive metastatic breast cancer who had been randomly assigned to receive the aromatase inhibitor anastrozole plus the selective estrogen-receptor down-regulator fulvestrant, as compared with anastrozole alone, as first-line therapy. We now report final survival outcomes.
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Abstract Background: A clinically significant improvement in median overall survival (OS) has been reported for fulvestrant 500 mg vs fulvestrant 250 mg (26.4 months vs 22.3 months, respectively; hazard ratio [HR] 0.81; 95% confidence interval (CI) 0.69, 0.96; nominal p=0.02) in the Phase III COmparisoN of Faslodex In Recurrent or Metastatic breast cancer (CONFIRM) study, following failure on prior endocrine therapy. Therefore, further evidence for OS effects of fulvestrant 500 mg was sought. The Fulvestrant fIRst-line Study comparing endocrine Treatments (FIRST) compares fulvestrant 500 mg with anastrozole in the earlier first-line treatment setting for postmenopausal women with hormone receptor-positive (HR+) advanced breast cancer. In the primary analysis (6 months after last patient was randomized) fulvestrant 500 mg was at least as effective as anastrozole for clinical benefit rate (primary endpoint) and showed a significantly longer time to progression (TTP; median TTP not reached for fulvestrant 500 mg vs 12.5 months for anastrozole; HR 0.63; 95% CI 0.39, 1.00; p=0.05). In a follow-up analysis when 79.5% of patients (pts) had discontinued study treatment, median TTP was 23.4 months for fulvestrant 500 mg vs 13.1 months for anastrozole (HR 0.66; 95% CI 0.47, 0.92; p=0.01). Here we report OS from FIRST. Methods: FIRST is a Phase II, randomized, open-label, multicenter study (NCT00274469) comparing fulvestrant 500 mg (500 mg im on Days 0, 14 and 28, and every 28 days thereafter) with anastrozole (1 mg/day po). Pts were postmenopausal women with locally advanced or metastatic HR+ breast cancer who had not received prior endocrine therapy for locally advanced or metastatic disease. Kaplan-Meier curves of OS (time from randomization to death from any cause) will be compared by unadjusted log-rank test. Pts not known to have died including those lost to follow-up or with no survival information will be right-censored at last known date alive. Serious adverse events will also be reported. Results: In total, 205 pts (median age 67.0 years) were randomized from 62 centers in 9 countries (fulvestrant 500 mg: n=102; anastrozole: n=103). The first pt enrolled on Feb 6, 2006. As of May 14, 2014, 40/205 pts (19.5%) were alive across both treatment groups. 4 pts (2.0%) were lost to follow-up, 130 pts (63.4%) had died, and 31 pts [15.1%] did not participate in the OS follow-up (20 pts due to non-participation of center in the OS follow-up; other reasons included withdrawal of consent). A total of 130 events had occurred; preliminary data indicate a median OS of 50 months in the total study population. Data cut-off is planned for when approximately 65% pts have died, expected in Aug 2014. Comparative data between fulvestrant 500 mg and anastrozole for OS will be presented. Conclusions: We understand FIRST to be the only study that has demonstrated improved efficacy (ie TTP) for an alternative hormone therapy over a third-generation aromatase inhibitor for treatment of HR+ advanced breast cancer. Improved OS results would provide additional support for superior efficacy of fulvestrant 500 mg over anastrozole as first-line endocrine therapy for postmenopausal women with HR+ locally advanced or metastatic breast cancer. Citation Format: John FR Robertson, Antonio Llombart-Cussac, David Feltl, John Dewar, Marek Jasiówka, Nicola Hewson, Yuri Rukazenkov, Matthew J Ellis. Fulvestrant 500 mg versus anastrozole as first-line treatment for advanced breast cancer: Overall survival from the Phase II ‘FIRST’ study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S6-04.
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To compare the clinical activity of the pure antiestrogen fulvestrant at 500 mg/mo (double the approved dose) with the aromatase inhibitor anastrozole as first-line endocrine therapy for advanced hormone receptor-positive breast cancer in postmenopausal women.FIRST (Fulvestrant First-Line Study Comparing Endocrine Treatments) is a phase II, randomized, open-label, multicenter study of a fulvestrant high-dose (HD) regimen (500 mg/mo plus 500 mg on day 14 of month 1) versus anastrozole (1 mg/d). The primary efficacy end point was clinical benefit rate (CBR), defined as the proportion of patients experiencing an objective response (OR) or stable disease for > or = 24 weeks. The primary analysis was performed 6 months after the last patient was randomly assigned.CBR was similar for fulvestrant HD (n = 102) and anastrozole (n = 103), 72.5% v 67.0%, respectively (odds ratio, 1.30; 95% CI, 0.72 to 2.38; P = .386). Objective response rate (ORR) was also similar between treatments: fulvestrant HD, 36.0%; anastrozole, 35.5%. Time to progression (TTP) was significantly longer for fulvestrant versus anastrozole (median TTP not reached for fulvestrant HD v 12.5 months for anastrozole; hazard ratio, 0.63; 95% CI, 0.39 to 1.00; P = .0496). Duration of OR and CB also numerically favored fulvestrant HD. Both treatments were well tolerated, with no significant differences in the incidence of prespecified adverse events.First-line fulvestrant HD was at least as effective as anastrozole for CBR and ORR and was associated with significantly longer TTP. Fulvestrant HD was generally well tolerated, with a safety profile similar to that of anastrozole.
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The aromatase inhibitor anastrozole inhibits estrogen synthesis. Fulvestrant binds and accelerates degradation of estrogen receptors. We hypothesized that these two agents in combination might be more effective than anastrozole alone in patients with hormone-receptor (HR)-positive metastatic breast cancer.
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