Zoladex® (goserelin acetate implant)

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Overall survival for patients with HR+ breast cancer is similar for Zoladex® and oophorectomy*9

Overall survival

Chart showing overall survival with Zoladex vs oophorectomy Chart showing overall survival with Zoladex vs oophorectomy
  • *Overall survival (OS) and failure-free survival (FFS) were similar in the 2 treatment groups. OS=(HR 0.86; 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.

Study design

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.9

Estrogen levels on Zoladex Endocrine therapy vs ovarian suppression Side effects

Zoladex suppresses estrogen to postmenopausal levels9

Comparison of estrogen levels
(8 weeks of Zoladex treatment)

Comparison of estrogen chart Comparison of estrogen chart
Study design

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.9

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.
Study design

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

National Comprehensive Cancer Network® (NCCN®) recommends 5 years of ovarian suppression in women at higher risk of recurrence5

In the treatment of breast cancer, NCCN® recommends ovarian ablation or 5 years of ovarian suppression as adjuvant endocrine therapy in premenopausal women with HR-positive breast cancer at higher risk of recurrence (ie, young age, high-grade tumor, lymph node involvement).5

Category 1 evidence§

  • §Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
  • Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.2.2017. © 2017 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data become available.

Estrogen-reducing strategies provide complementary effects11

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
References
  1. ZOLADEX® (goserelin acetate implant) 3.6 mg [prescribing information]. Lake Forest, IL: TerSera Therapeutics LLC; 2017.
  2. LUPRON DEPOT® (leuprolide acetate for depot suspension) [prescribing information]. North Chicago, IL: AbbVie Inc.; 2018.
  3. ELIGARD® (leuprolide acetate) [prescribing information]. Fort Collins, CO: Tolmar Pharmaceuticals Inc.; 2018.
  4. TRELSTAR® (triptorelin pamoate for injectable suspension) [prescribing information]. Irvine, CA: Allergan, Inc.; 2018.
  5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.3.2018. © National Comprehensive Cancer Network, Inc 2018. All rights reserved. Accessed December 28, 2018. To view the most recent and complete version of the guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.
  6. Moser MA. Engineering out needle stick injuries (safety devices). The Safe Angle. Summer 2004;5-7.
  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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.

Important Safety Information about ZOLADEX

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. Woman 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 prostate and 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

Androgen deprivation therapy 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

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

The most commonly observed adverse reactions during ZOLADEX treatment for prostatic carcinoma were due to the expected physiological effects from decreased testosterone levels. The most common adverse reactions (incidence of >5% in prostate clinical trials) were:

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

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

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

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088 or contact TerSera Therapeutics at 1-844-334-4035 or medicalinformation@tersera.com.