104. Randomized phase III study of the new selective aromatase inhibitor arimidex (A) (ZD1033) versus megestrol acetate (MA) in the treatment of postmenopausal women with advanced breast cancer

PURPOSE To compare the efficacy and tolerability of anastrozole (1 and 10 mg once daily), a selective, oral, nonsteroidal aromatase inhibitor, and megestrol acetate (40 mg four times daily), in postmenopausal women who progressed following tamoxifen treatment. PATIENTS AND METHODS Two randomized, double-blind for anastrozole, open-label for megestrol acetate, parallel-group, multicenter trials were conducted in 764 patients. Because both trials were identical in design, an analysis of the combined results was performed to strengthen interpretation of results from each trial. RESULTS The median follow-up duration was approximately 6 months. The estimated progression hazards ratios were 0.97 (97.5% confidence interval [CI], 0.75 to 1.24) for anastrozole 1 mg versus megestrol acetate and 0.92 (97.5% CI, 0.71 to 1.19) for anastrozole 10 mg versus megestrol acetate. The overall median time to progression was approximately 21 weeks. Approximately one third of patients in each group benefited from treatment. Twenty-seven patients (10.3%) in the anastrozole 1-mg group, 22 (8.9%) in the anastrozole 10-mg group, and 20 (7.9%) in the megestrol acetate group had a complete or partial response, and 66 (25.1%), 56 (22.6%), and 66 (26.1%) patients, respectively, had stable disease for > or = 24 weeks. For all end points, individual trial results were similar to the results of the combined analysis. Anastrozole and megestrol acetate were well tolerated. Gastrointestinal disturbance was more common among patients in the anastrozole groups than the megestrol acetate group; the difference between the anastrozole 10 mg and megestrol acetate groups was significant (P = .005). Significantly fewer patients in the anastrozole 1-mg (P < .0001) and 10-mg (P < .002) groups had weight gain than in the megestrol acetate group. More than 30% of megestrol acetate-treated patients had weight gain > or = 5%, and 10% of patients had weight gain > or = 10%. Patients who received megestrol acetate continued to gain weight over time. CONCLUSION Anastrozole, 1 and 10 mg once daily, is well tolerated and as effective as megestrol acetate in the treatment of postmenopausal women with advanced breast cancer who progressed following tamoxifen treatment. Moreover, anastrozole therapy avoids the weight gain associated with megestrol acetate treatment.

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3. A randomized trial of the new specific aromatase inhibitor ‘Arimidex’ (anastrozole) versus megestrol acetate (MA) in the treatment of postmenopausal women with advanced breast cancer (ABC)

The Breast ◽

10.1016/0960-9776(95)90095-0 ◽

1995 ◽

Vol 4 (3) ◽

pp. 227-228

Author(s):

W. Jonat ◽

A. Howell ◽

C.P. Blomqvist ◽

W. Eiermann ◽

G. Winblad ◽

...

Keyword(s):

Breast Cancer ◽

Advanced Breast Cancer ◽

Randomized Trial ◽

Aromatase Inhibitor ◽

Postmenopausal Women ◽

Advanced Breast ◽

Megestrol Acetate

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Phase III, Multicenter, Double-Blind, Randomized Study of Letrozole, an Aromatase Inhibitor, for Advanced Breast Cancer Versus Megestrol Acetate

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.14.3357 ◽

2001 ◽

Vol 19 (14) ◽

pp. 3357-3366 ◽

Cited By ~ 264

Author(s):

A. Buzdar ◽

J. Douma ◽

N. Davidson ◽

R. Elledge ◽

M. Morgan ◽

...

Keyword(s):

Breast Cancer ◽

Treatment Failure ◽

Advanced Breast Cancer ◽

Disease Progression ◽

Postmenopausal Women ◽

Advanced Breast ◽

Megestrol Acetate ◽

Phase Iii ◽

Double Blind ◽

Antiestrogen Therapy

PURPOSE: To compare two doses of letrozole (0.5 mg and 2.5 mg every day) and megestrol acetate (40 mg qid) as endocrine therapy in postmenopausal women with advanced breast cancer previously treated with antiestrogens. PATIENTS AND METHODS: This double-blind, randomized, multicenter, multinational study enrolled 602 patients, all of whom were included in the primary analysis in the protocol. Patients had advanced or metastatic breast cancer with evidence of disease progression while receiving continuous adjuvant antiestrogen therapy, had experienced relapse within 12 months of stopping adjuvant antiestrogen therapy given for at least 6 months, or had experienced disease progression while receiving antiestrogen therapy for advanced disease. Tumors were required to be estrogen receptor– and/or progesterone receptor–positive or of unknown status. Confirmed objective response rate was the primary efficacy variable. Karnofsky Performance Status and European Organization for Research and Treatment of Cancer quality-of-life assessments were collected for 1 year. RESULTS: There were no statistically significant differences among the three treatment groups for overall objective tumor response. Patients treated with letrozole 0.5 mg had improvements in disease progression (P = .044) and a decreased risk of treatment failure (P = .018), compared with patients treated with megestrol acetate. Letrozole 0.5 mg showed a trend (P = .053) for survival benefit when compared with megestrol acetate. Megestrol acetate was more likely to produce weight gain, dyspnea, and vaginal bleeding, and the letrozole groups were more likely to experience headache, hair thinning, and diarrhea. CONCLUSION: Given a favorable tolerability profile, once-daily dosing, and evidence of clinically relevant benefit, letrozole is equivalent to megestrol acetate and should be considered for use as an alternative treatment of advanced breast cancer in postmenopausal women after treatment failure with antiestrogens.

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MONARCH plus: abemaciclib plus endocrine therapy in women with HR+/HER2– advanced breast cancer: the multinational randomized phase III study

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920963925 ◽

2020 ◽

Vol 12 ◽

pp. 175883592096392

Author(s):

Qing Yuan Zhang ◽

Tao Sun ◽

Yong Mei Yin ◽

Hui Ping Li ◽

Min Yan ◽

...

Keyword(s):

Breast Cancer ◽

Advanced Breast Cancer ◽

Postmenopausal Women ◽

Endocrine Therapy ◽

Hazard Ratio ◽

Advanced Breast ◽

Phase Iii ◽

Meaningful Improvement ◽

Measurable Disease ◽

Phase Iii Study

Aim: To compare the efficacy, safety, and tolerability of abemaciclib plus endocrine therapy (ET) versus ET alone in postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) from China, Brazil, India, and South Africa. Methods: This randomized, double-blind, phase III study was conducted between 9 December 2016 and 29 March 2019. Postmenopausal women with HR-positive, HER2-negative ABC with no prior systemic therapy in an advanced setting (cohort A) or progression on prior ET (cohort B) received abemaciclib (150 mg twice daily) or placebo plus: anastrozole (1 mg/day) or letrozole (2.5 mg/day) (cohort A) or fulvestrant (500 mg per label) (cohort B). The primary endpoint was progression-free survival (PFS) in cohort A, analyzed using the stratified log-rank test. Secondary endpoints were PFS in cohort B (key secondary endpoint), objective response rate (ORR), and safety. This interim analysis was planned after 119 PFS events in cohort A. Results: In cohort A, 207 patients were randomly assigned to the abemaciclib arm and 99 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: not reached versus 14.7 months; hazard ratio 0.499; 95% confidence intervals (CI) 0.346–0.719; p = 0.0001). ORR was 65.9% in the abemaciclib arm and 36.1% in the placebo arm ( p < 0.0001, measurable disease population). In cohort B, 104 patients were randomly assigned to the abemaciclib arm and 53 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: 11.5 versus 5.6 months; hazard ratio 0.376; 95% CI 0.240–0.588; p < 0.0001). ORR was 50.0% in the abemaciclib arm and 10.5% in the placebo arm ( p < 0.0001, measurable disease population). The most frequent grade ⩾3 adverse events in the abemaciclib arms were neutropenia, leukopenia, and anemia (both cohorts), and lymphocytopenia (cohort B). Conclusion: The addition of abemaciclib to ET demonstrated significant and clinically meaningful improvement in PFS and ORR, without new safety signals observed in this population. Trial Registration: ClinicalTrials.gov identifier: NCT02763566.

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AMEERA-5: A randomized, double-blind phase III study of amcenestrant (SAR439859) + palbociclib versus letrozole + palbociclib for previously untreated ER+/HER2- advanced breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps1104 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS1104-TPS1104

Author(s):

Aditya Bardia ◽

Javier Cortes ◽

Sara A. Hurvitz ◽

Suzette Delaloge ◽

Hiroji Iwata ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Phase I ◽

Advanced Breast Cancer ◽

Progression Free Survival ◽

Advanced Breast ◽

Phase Iii ◽

Double Blind ◽

Free Survival ◽

Phase Iii Study

TPS1104 Background: Selective estrogen receptor degraders (SERDs) block estrogen receptor (ER) associated signaling and have created interest for treating patients (pts) with advanced ER+ breast cancer (BC). Fulvestrant is currently the only SERD available for advanced BC but requires intramuscular administration, limiting the applied dose, exposure and receptor engagement. Amcenestrant (SAR439859) is an oral SERD that binds with high affinity to both wild-type and mutant ER, blocking estradiol binding and promoting up to 98% ER degradation in preclinical studies. In the phase I AMEERA-1 study of pretreated pts with ER+/HER2- advanced BC, amcenestrant 150–600 mg once daily (QD) showed a mean ER occupancy of 94% with plasma concentrations > 100 ng/mL and a favorable safety profile (Bardia, 2019; data on file). Combination therapy with amcenestrant + palbociclib (palbo) was also evaluated as part of this ongoing phase I study. CDK 4/6 inhibitors (CDK4/6i) combined with an aromatase inhibitor (AI), the gold standard for first line treatment for advanced breast cancer, prolong progression free survival (PFS) in pts with no prior treatment for ER+/HER2- advanced BC, but OS benefit has not been shown yet in postmenopausal pts. There remains a clinical need for more effective treatments in this setting. Methods: AMEERA-5 (NCT04478266) is an ongoing, prospective, randomized, double-blind phase III study comparing the efficacy and safety of amcenestrant + palbo with that of letrozole + palbo in pts with advanced, locoregional recurrent or metastatic ER+/HER2- BC who have not received prior systemic therapy for advanced disease. The study includes men, pre/peri-menopausal (with goserelin) and post-menopausal women. Pts with progression during or within 12 months of (neo)adjuvant endocrine therapy using any of the following agents are excluded: AI, selective estrogen receptor modulators, CDK4/6i. Pts are randomized 1:1 to either continuous amcenestrant 200 mg or letrozole 2.5 mg QD orally with matching placebos; both combined with palbo 125 mg QD orally (d1–21 every 28-d cycle). Randomization is stratified according to disease type (de novo metastatic vs recurrent disease), the presence of visceral metastasis, and menopausal status. The primary endpoint is investigator assessed progression free survival (PFS) (RECIST v1.1). Secondary endpoints are overall survival, PFS2, objective response rate, duration of response, clinical benefit rate, pharmacokinetics of amcenestrant and palbo, health-related quality of life, time to chemotherapy, and safety. Biomarkers will be measured in paired tumor biopsies and cell free deoxyribonucleic acid (cfDNA) over time. Target enrolment = 1066 pts; enrolment as of 1/2021 = 33 pts. Bardia A, et al., J Clin Oncol. 2019; 37 (15 suppl):1054 Clinical trial information: NCT04478266 .

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