Abstract P5-12-07: Hormone dynamics, pharmacokinetics, safety and efficacy of leuprorelin acetate 6-month depot formulation and tamoxifen adjuvant endocrine therapy combination in premenopausal patients with hormone receptor-positive breast cancer
Authors: Kurebayashi J , Toyama T , Sumino S , Fujimoto T 
Published: May 2016

Abstract
Background: Luteinizing hormone-releasing hormone agonist + tamoxifen is standard postoperative adjuvant endocrine therapy for premenopausal patients with hormone receptor-positive breast cancer. Postoperative adjuvant endocrine therapy is now used for a longer period, and the longer-lasting leuprorelin acetate 6-month depot formulation (TAP-144-SR[6M]) is expected to increase patients' quality of life and decrease medical practitioners' burden.
Methods: The hormone dynamics, pharmacokinetics (PK), safety, and efficacy of TAP-144-SR(6M) were compared with those of the 3-month depot formulation (TAP-144-SR[3M]) in a 96-week, phase 3 open-label parallel-group comparison study in premenopausal breast cancer patients after surgery (ClinicalTrial.gov ID: NCT01546649). Inclusion criteria were estrogen receptor (ER) and/or progesterone receptor (PgR) positive; TNM classification of T1-T3, any N, M0; and premenopausal (menstruation confirmed within the previous 12 weeks or both follicle-stimulating hormone [FSH] &lt;40 mIU/mL and estradiol [E2] ≥10 pg/mL at enrollment). Patients were randomized to TAP-144-SR(6M) (6M group [6MG]) or TAP-144-SR(3M) (3M group [3MG]) based on number of axillary lymph node metastases, tumor size, age, ER/PgR status, chemotherapy or not, and study site. The primary endpoint was serum E2 suppression rate based on the menopausal level (≤30 pg/mL) from 4 to 48 weeks after the first administration. Secondary endpoints were serum hormone dynamics, efficacy (disease-free survival [DFS] and distance DFS [DDFS]), PK and safety. The planned number of patients was 164 (82 in each group).
Results: A total of 180 patients were enrolled from Apr 2012 to Feb 2013 and 167 patients were randomized. We compared 83 patients in 6MG (age: mean 44.2; SD 4.90) and 84 patients in 3MG (44.0; 5.18). There were no significant differences in background factors between the groups. 6MG showed non-inferior suppression of serum E2 levels to 3MG (See Table). Serum LH and FSH levels were also decreased. DFSs and DDFSs at 96 weeks after randomization were similar in both groups. A double-peak PK profile and sustainable release of the study drug for 24 weeks were found with 6MG. All-grade adverse events (AEs) occurred in 98.8% and 97.6% and grade 3 or higher AEs in 18.1% and 21.4% with 6MG and 3MG, respectively. There were no significant differences in lumbar spine bone mineral density change rates in both groups.
Table Serum E2 suppression rate based on the menopausal level (≤30 pg/mL) from 4 to 48 weeks after the first administration 6MG (n = 83)3MG (n = 84)Serum E2 suppression rate (%) (95% CI)97.6 (91.565, 99.707)96.4 (89.916, 99.257)6MG − 3MG (95% CI)1.2 (−5.241, 7.806)Note: Noninferiority margin of 10%.
Conclusion: This first clinical study of TAP-144-SR(6M) in premenopausal breast cancer patients showed clinically noninferior serum E2 suppression levels to TAP-144-SR(3M), and no significant safety differences between the groups. TAP-144-SR(6M) was confirmed to have excellent usability in premenopausal breast cancer patients after surgery, and is considered valuable for the appropriate treatment of these patients.
Citation Format: Kurebayashi J, Toyama T, Sumino S, Fujimoto T. Hormone dynamics, pharmacokinetics, safety and efficacy of leuprorelin acetate 6-month depot formulation and tamoxifen adjuvant endocrine therapy combination in premenopausal patients with hormone receptor-positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-12-07.