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A Phase II Study of Everolimus in Combination With Exemestane Versus Everolimus Alone Versus Capecitabine in Advance Breast Cancer. (BOLERO-6)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01783444
Recruitment Status : Completed
First Posted : February 5, 2013
Last Update Posted : March 1, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
This was a three-arm, randomized, open label, multi-center phase II study investigating the combination of everolimus (10mg daily) with exemestane (25mg daily) versus everolimus (10mg daily) versus capecitabine (1250mg/m2 twice daily for 14 days, 3-week cycle) in patients with estrogen-receptor positive, HER2 negative, advanced breast cancer after recurrence or progression on letrozole or anastrozole.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Capecitabine Drug: Exemestane Drug: Everolimus Phase 2

Detailed Description:

The reference therapy (control arm) used in the course of this trial was the combination arm of everolimus plus exemestane. The investigational therapies in the context of this study were everolimus monotherapy and capecitabine monotherapy. All treatments were taken orally until disease progression, intolerable toxicity or withdrawal of patient's informed consent. Patients were randomly assigned with equal allocation to one of the treatment arms:

  1. Exemestane (25mg daily) in combination with everolimus (10mg daily)
  2. Everolimus (10mg daily)
  3. Capecitabine (1250mg/m2 twice daily) orally for two weeks, followed by a one week rest period in 3-weeks cycles.

Treatment assignment was stratified by the presence of visceral disease (yes vs. no). Visceral refered to lung, liver, heart, ovary, spleen, kidney, adrenal gland, malignant pleural or pericardial effusion or malignant ascites.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 317 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of Everolimus in Combination With Exemestane Versus Everolimus Alone Versus Capecitabine in the Treatment of Postmenopausal Women With ER+Locally Advanced, Recurrent, or Metastatic Breast Cancer After Recurrence or Progression on Prior Letrozole or Anastrozole.
Actual Study Start Date : February 26, 2013
Actual Primary Completion Date : July 2, 2018
Actual Study Completion Date : July 30, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Capecitabine Monotherapy
Capecitabine monotherapy arm (1250mg/m2 twice daily) orally for two weeks, followed by a one week rest period in 3-weeks cycles.
Drug: Capecitabine
Capecitabine, for oral use 1250 mg/m2 twice daily for 2 weeks followed by one week rest (3-week cycle). Capecitabine was locally supplied by the Investigator.
Other Name: Capecitabine monotherapy

Experimental: Everolimus Monotherapy
Everolimus (10mg daily).
Drug: Everolimus
Everolimus was centrally dispensed via IWRS. Everolimus was taken as oral tablets for oral use 10 mg (2 × 5 mg) daily.
Other Name: RAD001

Active Comparator: Everolimus with Exemestane
Everolimus (10mg daily) with exemestane (25mg daily).
Drug: Exemestane
Exemestane tablets of 25 mg was taken orally once per day. Dose modifications in the management of adverse events were allowed.
Other Name: Control Arm




Primary Outcome Measures :
  1. Progression Free Survival (PFS) - Everolimus plus exemestane versus everolimus alone [ Time Frame: 28 months after first patient randomized or once approximatly 150 PFS have occurred ]
    Progression Free Survival (PFS) is defined as the time from date of randomization to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm.


Secondary Outcome Measures :
  1. Progression Free Survival (PFS) - Everolimus plus exemestane versus Capecitabine alone [ Time Frame: 28 months after first patient randomized or once approximatly 150 PFS events have occured ]
    Progression Free Survival (PFS) is defined as the time from date of randomization to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm.

  2. Overall Survival (OS) [ Time Frame: Every 3 months following the end of study visit until 2015 (up to 3 years) ]
    Overall Survival (OS) is defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died by the date of analysis cut-off, OS was censored at the date of last known date patient alive.

  3. Overall Response Rate (ORR) [ Time Frame: From the date of first dose of study medication until the date of the first documented disease progression or date of death from any cause whichever came first, assessed for approximately for 28 months ]
    Overall Response Rate (ORR) is defined as the proportion of participants with best overall response of complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST 1.1. ORR was analyzed in the full population. Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for target/non target lesions: Complete Response (CR), disappearance of all target/non target lesions (all lymph nodes assigned as non-target lesions must be non-pathological in size (< 10 mm short axis)); Partial response (PR), >=30% decrease in the sum of the longest diameter of target lesions ; Overall Response (OR)= CR+PR. Only descriptive analysis.

  4. Clinical Benefit Rate (CBR) [ Time Frame: From the date of first dose of study medication until the date of the first documented disease progression or date of death from any cause whichever came first, assessed for approximately 28 months ]
    Clinical Benefit Rate (CBR) is defined as the proportion of participants with a best overall response of complete response (CR) or partial response (PR) or stable disease (SD) or Non-CR/non-PD lasting more than 24 weeks based on local investigator's assessment according to RECIST 1.1. Only descriptive analysis.

  5. Time to definitive deterioration in Eastern Cooperative Oncology Group (ECOG) performance status [ Time Frame: Baseline, Day 1, every 6 weeks for approximately 8 months ]
    The Eastern Cooperative Oncology Group (ECOG) Performance Status is a scale used to assess how a patient's disease is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis. The ECOG Performance Scores has 5 grades: 0 = fully active, able to carry on all pre-disease performance without restriction, 1 = restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work, 2 = ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50% of waking hours, 3 = capable of only limited self-care, confined to bed or chair more than 50% of waking hours, 4 = completely disabled, cannot carry on any self-care, totally confined to bed or chair and 5 = dead. Definitive deterioration is defined as no improvement in the ECOG status following observation of the deterioration.

  6. Time to 10% definitive deterioration in the global health status/Quality of life per EORTC-QLQ-C30 [ Time Frame: Baseline, every 6 weeks for approximately 8 months ]
    The global health status/QoL scale score of the QLQ-C30 is identified as the primary PRO variable of interest. Physical Functioning (PF), Emotional Functioning (EF) and Social Functioning (SF) scale scores of the QLQ-C30. The time to definitive 10% deterioration is defined as the time from the randomization date to the date of an event, which is defined as a worsening (decrease) in score by at least 10% compared to baseline, with no later increase above this threshold observed during the course of the study or death due to any cause. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high /healthy level of functioning, a high score for the global health status / QoL represents a high QoL.

  7. Mean change from Baseline in the global health status/Quality of life per EORTC module (BR23) at Weeks 12 and 24 [ Time Frame: Baseline, Week 12, Week 24 ]
    EORTC Quality of Life Questionnaire - Breast Cancer Module (EORTC QLQ-BR23) is to be used in conjunction with the EORTC QLQ-C30 for assessing the quality of life of breast cancer patients. Functional scales (Body image, Sexual functioning, Sexual enjoyment and Future perspective) and Symptoms scales/Items (Sytemic therapy side effects, Breast symptoms, Arm symptoms and Upset by hair loss) are scored as part of the BR-23. The scores are linearly converted to a 0-100 scale, where higher function scores reflect improved function and higher symptom scores present a higher level of symptoms.

  8. Mean change in Treatment Satisfaction Questionnaire for Medication (TSQM) between Week 3 and Week 12 [ Time Frame: Week 3, Week 12 ]
    The TSQM was developed and validated as a general measure for treatment satisfaction. It contains 14 items assessing the following 4 domains: effectiveness (sum of scores for questions 1 - 3), side effects (sum of scores for questions 4 - 8), convenience (sum of scores for questions 9 - 11) and Global Satisfaction (sum of scores for questions 12 - 14). The scores of the domain were added together and an algorithm was used to create a score of 0 to 100. Higher scores indicated greater satisfaction. A positive change from baseline indicates improvement.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

-Women with locally advanced, recurrent, or metastatic breast cancer along with confirmation of estrogen-receptor positive (ER+). Measurable disease defined as at least one lesion ≥ 10 mm by CT or MRI that can be accurately measured in at least one dimension (CT scan slice thickness ≤ 5 mm) OR • Bone lesions: lytic or mixed (lytic + blastic) in the absence of measurable disease as defined above

Key Exclusion Criteria:

-Patients who received more than one chemotherapy line. Patients with only non-measurable lesions other than lytic or mixed (lytic and blastic) bone metastasis.Previous treatment with exemestane, mTOR inhibitors, PI3K inhibitors or AKT inhibitors


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01783444


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Locations
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United States, California
University of California at Los Angeles Mattel Children's Hospital
Los Angeles, California, United States, 90095
University of California - Davis SC
Sacramento, California, United States, 95817
Sharp Memorial Hospital SharpClinicalOncologyResearch
San Diego, California, United States, 92123
United States, Florida
Florida Cancer Specialists Dept of Oncology (2)
Fort Myers, Florida, United States, 33901
Florida Cancer Specialists FL Cancer Specialists
Fort Myers, Florida, United States, 33901
United States, Maryland
Carroll Regional Cancer Center
Westminster, Maryland, United States, 21157
United States, Massachusetts
Lahey Clinic Dept of Lahey Clinic (2)
Burlington, Massachusetts, United States, 01805
New England Hematology/ Oncology Associates, P.C. SC
Newton, Massachusetts, United States, 02462
United States, Montana
Glacier View Research Institute - Cancer SC
Kalispell, Montana, United States, 59901
United States, New Jersey
Trinitas Comprehensive Cancer Center SC
Elizabeth, New Jersey, United States, 07207
Hackensack University Medical Center Dept of Oncology
Hackensack, New Jersey, United States, 07601
Rutgers-New Jersey Medical School SC
Newark, New Jersey, United States, 07101
United States, Ohio
Oncology Hematology Care Inc Oncology Hematology Care 2
Cincinnati, Ohio, United States, 45242
United States, Oklahoma
Oklahoma Cancer Specialists and Research Institute Oklahoma Cancer Specialists
Tulsa, Oklahoma, United States, 74136
United States, Tennessee
Chattanooga Oncology and Hematology Assoicates, PC Chattanooga Oncology
Chattanooga, Tennessee, United States, 37404
The Jones Clinic SC
Germantown, Tennessee, United States, 38138
University of Tennessee SC
Knoxville, Tennessee, United States, 27920-6969
Sarah Cannon Research Institute SC (2)
Nashville, Tennessee, United States, 37203
United States, Texas
The Center for Cancer and Blood Disorders Dept. of The Ctr for C & BD
Fort Worth, Texas, United States, 76104
United States, Virginia
University of Virginia Health Systems SC-4
Charlottesville, Virginia, United States, 22908-0334
United States, Washington
Northwest Medical Specialties Dept of Onc
Tacoma, Washington, United States, 98405
Argentina
Novartis Investigative Site
Caba, Buenos Aires, Argentina, C1025ABI
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Posadas, Misiones, Argentina
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Rosario, Santa Fe, Argentina, S2000KZE
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Rio Negro, Viedma, Argentina, 8500
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Cordoba, Argentina, X5016KEH
Australia, New South Wales
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Randwick, New South Wales, Australia, 2031
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Wahroonga, New South Wales, Australia, 2076
Australia, Victoria
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Malvern, Victoria, Australia, 3144
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Parkville, Victoria, Australia, 3050
Belgium
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Liege, Belgium, 4000
Brazil
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Salvador, BA, Brazil, 41253-190
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Porto Alegre, Rio Grande Do Sul, Brazil, 90610-000
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Natal, RN, Brazil, 59075 740
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Passo Fundo, RS, Brazil, 99010-260
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Sao Paulo, SP, Brazil, 01317-002
Denmark
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Aarhus, Denmark, 8000 C
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Copenhagen, Denmark, DK-2100
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Næstved, Denmark, DK-4700
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Odense C, Denmark, DK-5000
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Roskilde, Denmark, 4000
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Vejle, Denmark, 7100
Hungary
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Budapest, HUN, Hungary, 1145
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Debrecen, Hungary, 4032
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Nyiregyhaza, Hungary, 4400
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Tatabanya, Hungary, 2800
India
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Hyderabad, Andhra Pradesh, India, 500 034
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Pune, Maharashtra, India, 411013
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Kolkatta, West Bengal, India, 700 053
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Mumbai, India, 400 012
Ireland
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Limerick, Co Limerick, Ireland
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Dublin 4, Ireland
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Galway, Ireland
Lebanon
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Ashrafieh, Lebanon, 166830
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Beirut, Lebanon, 1107 2020
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Beirut, Lebanon
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Hazmieh, Lebanon, 470
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Saida, Lebanon, 652
Malaysia
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Kota Kinabalu, Sabah, Malaysia, 88586
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Kuala Lumpur, Malaysia, 59100
Peru
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Jesus Maria, Lima, Peru, 11
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San Borja, Lima, Peru, 41
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Surquillo, Lima, Peru, 34
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Arequipa, Peru
Russian Federation
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Arkhangelsk, Russian Federation, 163045
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Moscow, Russian Federation, 115478
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St Petersburg, Russian Federation, 197758
Spain
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Sevilla, Andalucia, Spain, 41013
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Barcelona, Catalunya, Spain, 08035
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Madrid, Spain, 28033
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Madrid, Spain, 28040
Sweden
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Eskilstuna, Sweden, SE-631 88
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Joenkoeping, Sweden, 551 85
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Stockholm, Sweden, SE-171 76
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Uppsala, Sweden, SE-751 85
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Vasteras, Sweden, 721 89
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Vaxjo, Sweden, SE-351 85
Thailand
Novartis Investigative Site
Songkla, Hat Yai, Thailand, 90110
Novartis Investigative Site
Muang Lopburi, Lopburi, Thailand, 15000
Novartis Investigative Site
Muang, Thailand, 40002
Turkey
Novartis Investigative Site
Adana, Turkey, 01330
Novartis Investigative Site
Istanbul, Turkey, 34303
Novartis Investigative Site
Izmir, Turkey, 35340
United Kingdom
Novartis Investigative Site
East Kilbride, United Kingdom, G75 8RG
Novartis Investigative Site
Middlesborough, United Kingdom, TS4 3BW
Novartis Investigative Site
Nottingham, United Kingdom, NG5 1PB
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01783444     History of Changes
Other Study ID Numbers: CRAD001Y2201
2012-003757-28 ( EudraCT Number )
First Posted: February 5, 2013    Key Record Dates
Last Update Posted: March 1, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com


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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Estrogen receptor positive, locally advanced, metastatic breast cancer, Everolimus, Exemestane, Capecitabine

Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Capecitabine
Everolimus
Sirolimus
Exemestane
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists