Overall survival for patients with HR+ breast cancer is similar for ZOLADEX and oophorectomy*8
Overall survival
*Overall survival (OS) and failure-free survival (FFS) were similar in the 2 treatment groups. OS=(HR 0.80; 95% CI, 0.53 - 1.20) FFS=(HR 0.73; 95% CI, 0.51 - 1.04). The test of a 50% improvement in OS and FFS due to oophorectomy was rejected at P values less than 0.006.
A prospective, randomized clinical trial in premenopausal women with metastatic HR-positive breast cancer that compared ZOLADEX (3.6 mg subcutaneously every 4 weeks) with oophorectomy. Prior chemotherapy or hormone therapy for metastatic disease was not allowed. The primary objective was to determine if ZOLADEX was equivalent to oophorectomy in its effect on failure-free survival and overall survival. Secondary objectives were to compare objective response rates and toxicities and to assess the endocrine effects of ZOLADEX.8
ZOLADEX suppresses estrogen to postmenopausal levels8
Comparison of estrogen levels
(8 weeks of ZOLADEX treatment)
A prospective, randomized clinical trial in premenopausal women with metastatic HR-positive breast cancer that compared ZOLADEX (3.6 mg subcutaneously every 4 weeks) with oophorectomy. Prior chemotherapy or hormone therapy for metastatic disease was not allowed. The primary objective was to determine if ZOLADEX was equivalent to oophorectomy in its effect on failure-free survival and overall survival. Secondary objectives were to compare objective response rates and toxicities and to assess the endocrine effects of ZOLADEX.8
Best objective response† comparable to oophorectomy‡1
| 22% | ZOLADEX |
| 12% | Oophorectomy |
- †Complete response + partial response.
‡Survival time (33.2 months vs 33.6 months for ZOLADEX and oophorectomy, respectively) and time to treatment failure (6.7 months vs 5.5 months for ZOLADEX and oophorectomy, respectively) were also similar in the 2 treatment groups.
A prospective, randomized clinical trial in premenopausal women with metastatic HR-positive breast cancer that compared ZOLADEX (3.6 mg subcutaneously every 4 weeks) with oophorectomy.1
Estrogen-reducing strategies provide complementary effects10
Endocrine therapy
| Therapy | Mechanism of action | |
|---|---|---|
| Tamoxifen | Selective estrogen receptor modulator reduces estrogen binding without affecting estrogen production | |
| Aromatase inhibitor | Inhibition of aromatase reduces estrogen synthesis from androgens |
Ovarian suppression/ablation
| Therapy | Mechanism of action | |
|---|---|---|
| GnRH agonist | Ovarian suppression blocks ovarian function | |
| Oophorectomy | Permanent removal of primary source of estrogen | |
| Ovarian irradiation | Permanent destruction of primary estrogen-producing cells |
The effects of ZOLADEX are reversible1
Unlike oophorectomy, where the ovaries are permanently removed, ovarian function typically returns after ending ZOLADEX treatments.
- Graphical representation of estradiol levels during ZOLADEX treatment and oophorectomy.
Safety and tolerability1
| ZOLADEX (N=57) | Oophorectomy (N=55) | |
|---|---|---|
| Adverse events | % of Patients | % of Patients |
| Hot flashes | 70 | 47 |
| Tumor flare | 23 | 4 |
| Nausea | 11 | 7 |
| Edema | 5 | 0 |
| Malaise/Fatigue/Lethargy | 5 | 2 |
| Vomiting | 4 | 7 |
- Adverse events reported in a controlled clinical trial (SWOG-8692) comparing ZOLADEX with oophorectomy in pre- and perimenopausal women with advanced breast cancer. In the phase II clinical trial program in 333 pre- and perimenopausal women with advanced breast cancer, hot flashes were reported in 75.9% of patients and decreased libido was reported in 47.7% of patients. Injection site reactions were reported in less than 1% of patients.1
A closer look at tumor flare:
Like other GnRH agonists, ZOLADEX initially causes transient increases in estrogen in the first few weeks of treatment1
- Chronic exposure to ZOLADEX subsequently leads to suppression of gonadotropin secretion
- Serum estradiol is suppressed to levels similar to those observed in postmenopausal women within 3 weeks following initial administration
- ZOLADEX® (goserelin implant) 3.6 mg. Prescribing Information. TerSera Therapeutics LLC.
- LUPRON DEPOT® (leuprolide acetate for depot suspension). Prescribing Information. AbbVie Inc.
- ELIGARD® (leuprolide acetate). Prescribing Information. Tolmar Pharmaceuticals Inc.
- TRELSTAR® (triptorelin pamoate for injectable suspension). Prescribing Information. Verity Pharmaceuticals, Inc.
- Moser MA. Engineering out needle stick injuries (safety devices). The Safe Angle. Summer 2004;5-7.
- Morgan G, Cooley C. Injection systems for two luteinising hormone-releasing hormone agonists: a comparative assessment of administration times and nurses’ perceptions. Eur J Oncol Nurs. 2005;9:334-340.
- Montgomery BS, Borwell JP, Higgins DM. Does needle size matter? Patient experience of luteinising hormone-releasing hormone analogue injection. Prostate Cancer Prostatic Dis. 2005;8:66-68.
- Taylor CW, Green S, Dalton WS, et al. Multicenter randomized clinical trial of goserelin versus surgical ovariectomy in premenopausal patients with receptor-positive metastatic breast cancer: an intergroup study. J Clin Oncol. 1998;16:994-999.
- De Vos FY, van Laarhoven HW, Laven JS, et al. Menopausal status and adjuvant hormonal therapy for breast cancer patients: a practical guideline. Crit Rev Oncol Hematol. 2012;84:252-260.
- Rossi L, Pagani O. Adjuvant endocrine therapy in breast cancer: evolving paradigms in premenopausal women. Curr Treat Options Oncol. 2017;18:28. doi:10.1007/s11864-017-0473-1.
- Im SA, Lu YS, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381:307-316.
- Loibl S, Turner NC, Ro J, et al. Palbociclib combined with fulvestrant in premenopausal women with advanced breast cancer and prior progression on endocrine therapy: PALOMA-3 results. Oncologist. 2017;22(9):1028-1038.
- VERZENIO® (abemaciclib). Prescribing Information. Eli Lilly and Company.
Important Safety Information
Anaphylactic reactions to ZOLADEX have been reported in the medical literature. ZOLADEX is contraindicated in patients with a known hypersensitivity to GnRH, GnRH agonist analogues, or any of the components in ZOLADEX.
ZOLADEX is contraindicated during pregnancy unless used for palliative treatment of advanced breast cancer. ZOLADEX can cause fetal harm when administered to a pregnant woman. If used during pregnancy, the patient should be apprised of the potential hazard to the fetus. There is an increased risk for pregnancy loss due to expected hormonal changes that occur with ZOLADEX treatment. ZOLADEX should not be given to women with undiagnosed abnormal vaginal bleeding.
Pregnancy must be excluded for use in benign gynecological conditions. Women should be advised against becoming pregnant while taking ZOLADEX. Effective nonhormonal contraception must be used by all premenopausal women during ZOLADEX therapy and for 12 weeks following discontinuation of therapy.
Transient worsening of tumor symptoms, or the occurrence of additional signs and symptoms of breast cancer, may occasionally develop during the first few weeks of treatment. Some patients may experience a temporary increase in bone pain. Monitor patients at risk for complications of tumor flare.
Hyperglycemia and an increased risk of developing diabetes or worsening of glycemic control in patients with diabetes have been reported in men receiving GnRH agonists like ZOLADEX. Monitor blood glucose levels and glycosylated hemoglobin (HbA1c) periodically and manage according to current clinical practice.
Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists like ZOLADEX in men. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice.
Hypercalcemia has been reported in some breast cancer patients with bone metastases after starting treatment with ZOLADEX. If hypercalcemia does occur, appropriate treatment measures should be initiated.
Hypersensitivity, antibody formation and acute anaphylactic reactions have been reported with GnRH agonist analogues.
ZOLADEX may cause an increase in cervical resistance. Therefore, caution is recommended when dilating the cervix for endometrial ablation.
GnRH agonists may prolong the QT/QTc interval. Providers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes.
Injection site injury and vascular injury including pain, hematoma, hemorrhage and hemorrhagic shock, requiring blood transfusions and surgical intervention, have been reported with ZOLADEX. Extra care should be taken when administering ZOLADEX to patients with low BMI and/or to patients receiving full dose anticoagulation.
Depression may occur or worsen in women receiving GnRH agonists.
Treatment with ZOLADEX may be associated with a reduction in bone mineral density over the course of treatment. Data suggest a possibility of partial reversibility. In women, current available data suggest that recovery of bone loss occurs on cessation of therapy in the majority of patients.
In women, the most frequently reported adverse reactions were related to hypoestrogenism. The adverse reaction profile was similar for women treated for breast cancer, dysfunctional uterine bleeding, and endometriosis.
The most commonly reported adverse reactions with ZOLADEX in clinical trials for endometriosis were: hot flashes (96%), vaginitis (75%), headache (75%), decreased libido (61%), emotional lability (60%), depression (54%), sweating (45%), acne (42%), breast atrophy (33%), seborrhea (26%), and peripheral edema (21%).
The most commonly reported adverse reactions with ZOLADEX in clinical trials for endometrial thinning were: vasodilation/hot flashes (57%), headache (32%), sweating (16%), and abdominal pain (11%).
The most commonly reported adverse reactions with ZOLADEX in breast cancer clinical trials were hot flashes (70%), decreased libido (47.7%), tumor flare (23%), nausea (11%), edema (5%), and malaise/fatigue/lethargy (5%). Injection site reactions were reported in less than 1% of patients.
For ZOLADEX 3.6 mg: Hot flashes (62%), sexual dysfunction (21%), decreased erections (18%), lower urinary tract symptoms (13%), lethargy (8%), pain (worsened in the first 30 days) (8%), edema (7%), upper respiratory infection (7%), rash (6%), and sweating (6%).
For ZOLADEX 10.8 mg: Hot flashes (64%), pain (general) (14%), gynecomastia (8%), pelvic pain (6%), and bone pain (6%).
In the locally advanced carcinoma of the prostate clinical trial, additional adverse event data were collected for the combination therapy with radiation group during both the hormonal treatment and hormonal treatment plus radiation phases of this study. Adverse experiences (incidence >5%) in both phases of this study were hot flashes (46%), diarrhea (40%), nausea (9%), and skin rash (8%). Treatment with ZOLADEX and flutamide did not add substantially to the toxicity of radiation treatment alone.
Indications
ZOLADEX 3.6 mg and ZOLADEX 10.8 mg
Management of locally confined Stage T2b-T4 (Stage B2-C) carcinoma of the prostate in combination with flutamide. Treatment with ZOLADEX and flutamide should start 8 weeks prior to initiating radiation therapy and continue during radiation therapy.
Palliative treatment of advanced carcinoma of the prostate.
ZOLADEX 3.6 mg
Management of endometriosis, including pain relief and reduction of endometriotic lesions for the duration of therapy. Experience with ZOLADEX for the management of endometriosis has been limited to women 18 years of age and older treated for 6 months.
Use as an endometrial-thinning agent prior to endometrial ablation for dysfunctional uterine bleeding.
Palliative treatment of advanced breast cancer in pre- and perimenopausal women.
To report suspected adverse reactions, contact the FDA at 1‑800‑FDA‑1088 or www.FDA.gov/medwatch. You may also contact TerSera Therapeutics at 1‑844‑334‑4035 or medicalinformation@tersera.com.
Please see Full Prescribing Information for ZOLADEX 3.6 mg and ZOLADEX 10.8 mg.