GnRH Antagonist for Optimal Ovarian Suppression in Breast Cancer

Ovarian function suppression (OFS) is an important part of endocrine treatment for premenopausal women with advanced and early hormone receptor (HR)-positive breast cancer. Achievement of postmenopausal status through OFS is mandatory for treatment with aromatase inhibitors in premenopausal patients. Gonadotropin-releasing hormone (GnRH) agonists (eg, triptorelin, goserelin, leuprolide) are commonly used for ovarian suppression in premenopausal patients with HR-positive breast cancer; however, approximately 20% of patients fail to maintain complete ovarian suppression. Degarelix is a GnRH antagonist that blocks GnRH receptors in the pituitary gland and lead to decreased secretion of gonadotropins. Based on rapid suppression of testosterone to castration level, this agent is approved for use as androgen deprivation therapy in prostate cancer, but its role for OFS in premenopausal women with breast cancer has not been investigated.

In the randomized International Breast Cancer Study Group (IBCSG) phase II TREND trial (N = 51), the activity of neoadjuvant therapy with degarelix plus letrozole was compared to triptorelin plus letrozole in premenopausal women with early stage (cT2-T4b, any nodal status), HR-positive (ER and PR >50%), HER2-negative breast cancer. The primary endpoint of the study was time to optimal OFS, defined as the time from the first injection of degarelix or triptorelin until the first occurrence of a centrally assessed E2 level in the range of optimal OFS (≤2.72 pg/mL or ≤10 pmol/L) during the six 28-day cycles of neoadjuvant endocrine therapy (NET).

All patients achieved optimal OFS, regardless of treatment, by the end of cycle 1 (29 days). However, patients receiving degarelix in combination with letrozole achieved optimal OFS three times faster than those receiving triptorelin plus letrozole (3 days vs 14 days; HR 3.05, P<.001). Importantly, treatment with degarelix was associated with sustained OFS for all subsequent cycles, while suboptimal OFS (E2 level >2.72 pg/mL) was observed in 15.4% of patients receiving triptorelin.

Among 49 patients who underwent surgery following completion of NET, 38.8% had node-negative disease, with higher rates of node-negative disease being observed among patients treated with degarelix plus letrozole than those treated with triptorelin plus letrozole (43.5% vs 34.6%). The objective response rate (ORR) was similar between the two treatment groups (44.6% vs 46.2%). However, more patients in degarelix group underwent breast conserving surgery (52.2% vs 42.3%).

Adverse events (AEs) were as expected. There were no grade 4 AEs and the only two treatment-related grade 3 AEs were seen in patients receiving triptorelin plus letrozole (hypertension and anemia). The most common AEs associated with degarelix plus letrozole compared to triptorelin plus letrozole were hot flashes (80% vs 69.2%), arthralgia (32% vs 53.8%), insomnia (24% vs 11.5%), injection site reaction (24% vs 0%), hypertension (12% vs 3.8%), and nausea (16% vs 3.8%), all of grade 1/2. Among patient-reported endocrine symptoms, hot flashes were reported as the most burdensome symptoms associated with degarelix.

The investigators concluded that degarelix is more effective than triptorelin in inducing and maintaining OFS in premenopausal women undergoing treatment with letrozole for locally advanced HR-positive breast cancer. They highlighted that this may have “significant clinical value not only for women treated in the neoadjuvant setting, but also in adjuvant and metastatic settings.”

J Clin Oncol. 2018 Dec 27. [Epub ahead of print].

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