original report Neoadjuvant Degarelix Versus Triptorelin in Premenopausal Patients Who Receive Letrozole for Locally Advanced Endocrine-Responsive Breast Cancer: A Randomized Phase II Trial Silvia Dellapasqua, MD1; Kathryn P. Gray, PhD2; Elisabetta Munzone, MD1; Daniela Rubino, MD3; Lorenzo Gianni, MD4; Harriet Johansson, PhD, MSc1; Giuseppe Viale, MD1;KarinRibi,PhD,MPH5;Jurg¨ Bernhard, PhD5; Roswitha Kammler5; Rudolf Maibach, PhD5; Manuela Rabaglio-Poretti, MD5; Barbara Ruepp, PharmD5; Angelo Di Leo, MD, PhD6;AlanS.Coates,MD7; Richard D. Gelber, PhD8,9; Meredith M. Regan, ScD9; Aron Goldhirsch, MD1; and Marco Colleoni, MD1, for the International Breast Cancer Study Group abstract PURPOSE To evaluate endocrine activity in terms of ovarian function suppression (OFS) of degarelix (a gonadotropin-releasing hormone [GnRH] antagonist) versus triptorelin (a GnRH agonist) in premenopausal patients receiving letrozole as neoadjuvant endocrine therapy for breast cancer. PATIENTS AND METHODS Premenopausal women with stage cT2 to 4b, any N, M0; estrogen receptor and progesterone receptor greater than 50%; human epidermal growth factor receptor 2–negative breast cancer were randomly assigned to triptorelin 3.75 mg administered intramuscularly on day 1 of every cycle or degarelix 240 mg administered subcutaneously (SC) on day 1 of cycle 1 then 80 mg SC on day 1 of cycles 2 through 6, both with letrozole 2.5 mg/day for six 28-day cycles. Surgery was performed 2 to 3 weeks after the last injection. ASSOCIATED Serum was collected at baseline, after 24 and 72 hours, at 7 and 14 days, and then before injections on cycles 2 CONTENT through 6. The primary end point was time to optimal OFS (time from the first injection to first assessment of Appendix centrally assessed estradiol level # 2.72 pg/mL [# 10 pmol/L] during neoadjuvant therapy). The trial had 90% Data Supplement power to detect a difference using a log-rank test with a two-sided a of .05. Secondary end points included Author affiliations response, tolerability, and patient-reported endocrine symptoms. and support information (if RESULTS Between February 2014 and January 2017, 51 patients were enrolled (n = 26 received triptorelin plus applicable) appear letrozole; n = 25 received degarelix plus letrozole). Time to optimal OFS was three times faster for patients at the end of this assigned to degarelix and letrozole than to triptorelin and letrozole (median, 3 v 14 days; hazard ratio, 3.05; 95% article. CI, 1.65 to 5.65; P , .001). Furthermore, OFS was maintained during subsequent cycles for all patients Accepted on October assigned to receive degarelix and letrozole, whereas 15.4% of patients assigned to receive triptorelin and 19, 2018 and letrozole had suboptimal OFS after cycle 1 (six events during 127 measurements). Adverse events as a result of published at jco.org on December 27, both degarelix plus letrozole and triptorelin plus letrozole were as expected. 2018: DOI https://doi. CONCLUSION In premenopausal women receiving letrozole for neoadjuvant endocrine therapy, OFS was org/10.1200/JCO.18. achieved more quickly and maintained more effectively with degarelix than with triptorelin. 00296 Written on behalf of J Clin Oncol 37. © 2018 by American Society of Clinical Oncology the International Breast Cancer Study INTRODUCTION pituitary gonadotropins. Several GnRH analogs have been Group. developed (eg, triptorelin, goserelin and leuprolide), and The pharmaceutical Ovarian function suppression (OFS) was the first form there are no apparent differences in their OFS capabil- company had no role of systemic treatment for advanced breast cancer.1 Its ities.5 Upon administration of GnRH agonists, an initial in the reporting or use as an adjuvant therapy was associated with im- interpretation of the stimulating action of the hypophysis occurs (flare effect), proved disease-free and overall survivals in patients trial other than the which eventually causes a sustained decrease in go- opportunity to review younger than age 50 years who had breast cancer.2 nadotropin secretion (downregulation) that can be ob- the manuscript Currently, for premenopausal patients with endocrine- before submission. served after approximately 10 days. For some patients, responsive breast cancer, OFS is considered an im- Clinical trial there can be a delay of 2 to 4 months until downregulation 3 information: portant aspect of treatment in the advanced disease of the gonadotropins occurs. Moreover, approximately 4 ClinicalTrials.gov, setting and in the adjuvant and neoadjuvant settings. 20% of women do not maintain complete OFS with GnRH NCT02005887; 6 EudraCT, Gonadotropin-releasing hormone (GnRH) analogs in- analogs and experience occasional elevations in estradiol 2012-005326-29. teract with the GnRH receptor and modify release of (E2) as a result of sporadic escapes from OFS. 1 Downloaded from ascopubs.org by Harvard Countway Library of Medicine on January 3, 2019 from 206.253.207.235 Copyright © 2019 American Society of Clinical Oncology. All rights reserved. Dellapasqua et al Degarelix (Firmagon; Ferring, Copenhagen, DK) is a GnRH 3.75 mg intramuscularly on day 1 of every cycle plus antagonist that binds to and blocks GnRH receptors in the letrozole 2.5 mg/day orally; or degarelix 240 mg sub- pituitary gland, which results in decreased secretion of cutaneously given as two subcutaneous injections of gonadotropins. In men, this leads directly to a rapid de- 120 mg on day 1 of cycle 1 followed by 80 mg on day 1 of crease in the production of testosterone, for which sup- cycles 2 through 6 plus letrozole. Letrozole was started on pression to castration levels is achieved within 1 to 3 days day 1, concurrent with triptorelin or degarelix. Trial treat- and remains sustained during treatment.7,8 Degarelix is ments were to start within 14 days of random assignment currently approved for the treatment of prostate cancer. and could be started at any time during the menstrual Data are not available for the use of degarelix in patients cycle. Definitive surgery was performed within 2 to 3 weeks with breast cancer. after the last administration of triptorelin or degarelix. After In premenopausal women, suppression of ovarian function postsurgery evaluation, no additional follow-up data were with degarelix might be faster than with GnRH analogs and collected within the trial. Postsurgical treatments were optimally maintained throughout the treatment period. given at the discretion of the investigator. Random as- fi Neoadjuvant endocrine therapy (NET) is an excellent signment was strati ed according to age at random as- # v $ platform for the development of investigational drugs and signment ( 39 40 years). the exploration of novel combinations that can be de- Study visits occurred before every 28-day cycle for veloped in other clinical settings.9 6 months and required a physical exam, an Eastern Co- Limited data are available on NET in premenopausal pa- operative Oncology Group performance status, weight, and tients. In the Neoadjuvant Anastrozole Versus Tamoxifen in collection of adverse events (AEs; 31 targeted AEs and Patients Receiving Goserelin for Premenopausal Breast other grades 3 to 4 AEs according to Common Terminology Cancer (STAGE) trial, 204 premenopausal women were Criteria for AEs, version 4.0). Tumor evaluation by bilateral randomly assigned to receive goserelin 3.6 mg/month plus mammography and breast ultrasound and laboratory tests either anastrozole or tamoxifen for 24 weeks before surgery. (hematology, chemistry, carcinoembryonic antigen [CEA], More patients in the anastrozole group than in the ta- cancer antigen 15.3 [CA15.3]) were required at baseline, moxifen group had a complete or partial response (70.4% v after three cycles, and before surgery. Data about AEs and 50.5%, respectively).10 concomitant medications were also collected 30 days after surgery. Patients completed the 19-item Functional As- We therefore designed the TREND (Trial on the Endocrine sessment of Cancer Therapy, endocrine subscale (FACT- activity of Neoadjuvant Degarelix) trial (International Breast ES) at baseline, on day 1 of cycles 2 and 4, and before Cancer Study Group [IBCSG] 41-13), an open-label, two- surgery. arm, phase II, randomized study, to compare the endocrine activity of triptorelin versus degarelix in premenopausal E2, follicle-stimulating hormone (FSH), and luteinizing patients with breast cancer receiving letrozole as NET. hormone (LH) levels were determined in a central labo- ratory from serum samples collected at day 1 of the first treatment cycle before the administration of the first dose PATIENTS AND METHODS (baseline), at 24 and 72 hours, 7 days and 14 days after first Patients injection, and on day 1 of cycles 2 through 6. E2 con- centrations were measured by gas chromatography tan- fi Premenopausal women with histologically con rmed stage dem mass spectrometry detection after liquid-liquid cT2 to 4b, any nodal stage, M0; estrogen (ER) and pro- extraction. Duplicate standard curves, water blanks, and gesterone (PgR) receptor expression greater than 50%; four assay control pools were processed with samples to – human epidermal growth factor receptor 2 (HER2) neg- assess accuracy and precision of the assay. The lower limit ative (by immunohistochemistry and/or in situ hybridiza- of E2 level quantification was 0.625 pg/mL. Central pa- tion); invasive breast cancer were eligible. Premenopausal thology review of diagnostic biopsy and of the residual b status was determined locally as 17- -estradiol (ie, E2) surgical