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Degarelix quickly induces ovarian function suppression in neoadjuvant breast cancer regimen
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Premenopausal women treated with letrozole as neoadjuvant endocrine therapy for HER2-negative breast cancer attained faster and more sustained ovarian function suppression with degarelix than with triptorelin, according to results of a randomized phase 2 trial published in Journal of Clinical Oncology.
Degarelix (Firmagon, Ferring Pharmaceuticals), a gonadotropin-releasing hormone (GnRH) antagonist, is currently approved for treatment of prostate cancer, in which it has been shown to effectively suppress testosterone levels without testosterone surge or inducing clinical flare.
“In premenopausal women, suppression of ovarian function with degarelix might be faster than with gonadotropin-releasing hormone analogs and optimally maintained throughout the treatment period,” Silvia Dellapasqua, MD, of the European Institute of Oncology Istituto di Ricovero e Cura a Carattere Scientifico in Milan, and colleagues wrote. “Neoadjuvant endocrine therapy is an excellent platform for the development of investigational drugs and the exploration of novel combinations that can be developed in other clinical settings.”
In the open-label, two-arm, randomized phase 2 TREND trial, Dellapasqua and colleagues sought to compare the endocrine activity of degarelix with triptorelin, a GnRH agonist.
The study included 51 premenopausal women (mean age, 44 years; interquartile [IQR] range, 42-49) with HER2-negative invasive breast cancer with stage cT2 to 4b tumors, no distant metastases, and ER and PR expression greater than 50%.
The researchers randomly assigned the women to six 28-day cycles of neoadjuvant endocrine therapy with letrozole (Femara, Novartis) and either triptorelin 3.75 mg intermuscularly on day 1 of each cycle (n = 26) or degarelix 240 mg subcutaneously on day 1 of cycle 1 and 80 mg on day 1 of cycles 2 through 6 (n= 25). Each of the women received letrozole 2.5 mg daily for six cycles of 28 days, and all but two underwent surgery 2 to 3 weeks after the last treatment injection.
The researchers obtained blood samples at baseline, after 24 and 72 hours, at 7 and 14 days, and before injections on cycles 2 through 6.
Time to optimal ovarian function suppression (OFS) — from the initial injection to first evaluation of centrally assessed estradiol concentration of 2.72 pg/ml or less (10 pmol/L or less) during neoadjuvant therapy — served as the study’s primary endpoint. The trial used a log-rank test with a two-sided of .05 for 90% power to detect a difference between treatment groups. Secondary endpoints included response, tolerability and patient-reported endocrine symptoms.
All of the women achieved OFS by the end of the first treatment cycle.
Women assigned degarelix and letrozole attained optimal OFS three times faster than those assigned triptorelin and letrozole (median, 3 days vs. 14 days; HR = 3.95; 95% CI, 1.65-5.65). Moreover, all women in the degarelix group maintained OFS during subsequent cycles, whereas 15% in the triptorelin had suboptimal OFS after cycle 1 (6 events during 127 measurements).
A total of 45.1% of patients had partial responses and 47.1% had stable disease as the best overall response. The objective response rate for degarelix plus letrozole was 44% vs. 46.2% for triptorelin plus letrozole (difference, –2.2 percentage points; 90% CI, –25.1 to 20.8).
There were no grade 4 or unexpected adverse events related to either regimen. The most common adverse events in the degarelix vs. triptorelin groups included 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%).
Researchers noted potential study limitations, including the small number of patients enrolled and lack of post-surgery follow-up.
“In conclusion, in premenopausal women receiving letrozole for primary treatment of endocrine-responsive breast cancer, OFS was achieved more quickly and maintained more effectively with degarelix than with triptorelin throughout the neoadjuvant endocrine therapy period,” the researchers wrote. “These data support additional studies to assess whether degarelix improves disease control compared with the current standard of care in the treatment of premenopausal patients with breast cancer.” – by Jennifer Byrne
Disclosures: Dellapasqua reports travel, accommodations and expenses from Ipsen. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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The report by Dellapasqua and colleagues showing more rapid OFS with the GnRH antagonist degarelix compared with the GnRH agonist triporelin may have significant implications for breast cancer as it does in prostate cancer, where rapid suppression and avoidance of a “flare” reaction can be important in patients with critical lesions.
Ablation of ovarian function is an effective therapy used for decades and expanded with the availability of GnRH analogues, which have now been shown to improve survival when added to tamoxifen for both advanced and early-stage hormone-sensitive breast cancer. Doubling of PFS with the addition of cyclin-dependent kinase inhibitors to either aromatase inhibitors or fulvestrant (Faslodex, AstraZeneca) in postmenopausal patients with advanced disease has been shown to apply in premenopausal patients. Given the high response rates of 40% to 50% that are similar to those seen with chemotherapy, rapid ovarian suppression is a key objective in symptomatic disease.
The rapidity and sustainability of OFS and consistent effect across all patients treated are critical questions. Older trials comparing surgical or radiation ovarian ablation to GnRH analog treatment have shown equivalent outcomes in the advanced setting, but have been too underpowered to detect clinically relevant differences.
In the adjuvant setting, in the TEXT/SOFT trial, triptorelin suppressed estradiol to below the proposed target level 2.72 pg/mL in 25% of patients at 3 months, 24% at 6 months and 17% at 12 months.
It should also be noted that many other factors can effect postmenopausal estrogen level, including body mass, aromatase enzyme genotype and even the gut microbiome. The study by Dellapasqua and colleagues showed no difference in clinical response Preoperative Endocrine Prognostic Index, or PEPI, scores — the composite posttreatment pathologic stage/Ki67 score — but was not designed nor powered to compare outcomes.
Nevertheless, the more rapid suppression alone may call for additional study and its adoption in symptomatic premenopausal disease, and for high-risk early-stage disease, coupled with longer-term studies assessing endocrine profiles.
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Debu Tripathy, MD
HemOnc Today Editorial Board Member
The University of Texas MD Anderson Cancer Center
Disclosure: Tripathy reports research funding to his institution from Novartis, as well as fees from consultant/advisory roles with CellMax Life, Novartis and Pfizer.
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