Cardiovascular Events in GnRH Agonist vs. Antagonist

A Phase-II, Randomized, Assessor-Blind, Controlled Trial Comparing the Occurrence of Cardiovascular Events in Patients With Prostate Cancer and Cardiovascular Risk Factors Receiving Degarelix or GnRH Agonist

The purpose of this study is to test if the use of Degarelix for 1 year associated with a lower rate of cardiovascular toxicity compared to Gonadotropin-releasing hormone (GnRH) agonists in patients with advanced prostate cancer and cardiovascular risk factors, receiving combination therapy of Androgen deprivation therapy (ADT) and second line hormonal or chemotherapy?

Study Overview

• Status: Unknown
• Conditions: Prostate Cancer; Cardiac Event; Hormone Sensitive Prostate Cancer
• Intervention / Treatment: Drug: Degarelix; Drug: GnRH agonist

Detailed Description

Study design: Randomized phase-2, open label superiority study of the use of ADT combined with second line hormonal or chemotherapy in men with advanced prostate cancer and pre-existing cardiovascular risks.

Study population: Subjects with pre-existing cardiovascular risk with locally advanced or metastatic prostate cancer and scheduled to start ADT in combination with either second line hormonal or chemotherapy. We will exclude patients with use of ADT 6 months prior to randomization.

Intervention- Two initial loading doses of 120mg Degarelix for 1 month followed by 80mg monthly for eleven additional months.

Control- GnRH agonist at the discretion of the treating Urologist/Oncologist for 1 year.

Study Time line- The intervention phase will be for one year. During this year, follow-up visits will occur every 3 months. At each visit, we will assess the occurrence of cardiac-related events. In addition, Protein-specific Antigen (PSA) test will be performed each visit. At baseline, 3, 6 and 12 months cardiac biomarkers and lab measurements will be taken. Echocardiogram will be performed at baseline, 6, 9 and 12 months. In addition, cardio-vascular related events and hospitalizations will be monitored for additional 5 years.

Primary endpoint: To compare time to first cardiovascular event of patients with advanced prostate cancer treated for one year with Degarelix vs. GnRH agonist. This will be a composite outcome composed of: Death, Cerebrovascular accident (CVA), Myocardial infarction (MI), Transient ischemic attack (TIA), cardiac emergency room visits, heart catheterization.

Secondary endpoints: To compare time to first major adverse cardiovascular and cerebrovascular event (MACCE)- (Death, CVA, MI, heart catheterization with stent) as estimated by the cumulated probability at the 1-year timepoint of patients with advanced prostate cancer treated for one year with Degarelix vs. LHRH agonist. To compare cardiovascular biomarker levels of patients with advanced prostate cancer treated with Degarelix vs. GnRH agonist. To compare change in cardiac function as measured by Echocardiography in 6,9 and 12 months.

Study impact- This study has the potential to cause a paradigm shift. If we indeed demonstrate that Degarelix is associated with less cardiovascular toxicity with clinical significance, we expect that most urologist, as well as patients, will prefer Degarelix over all other ADT.

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Phase 2

Contacts and Locations

Study Locations

• Israel
  • Petah Tikva, Israel, 4941492
    • Rabin Medical Center - Beilinson Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. Locally advanced high-risk prostate cancer OR metastatic prostate cancer patients.

2. Patients are scheduled to receive a combination of either

   1. primary ADT for 12 months + either chemotherapy with docetaxel OR
   2. primary ADT for 12 months + second line hormonal treatment with abiraterone/ enzalutamide/ apalutamide

3. Patients with a medical history of either of the following:

   1. Myocardial infarction
   2. Ischaemic or haemorrhagic cerebrovascular conditions
   3. Arterial embolic and thrombotic events
   4. Ischaemic heart disease
   5. Prior coronary artery or iliofemoral artery revascularization (percutaneous or surgical procedures)
   6. Peripheral vascular disease (e.g. significant stenosis (ABPI<0.9), claudication, prior vascular surgery/intervention(
   7. Two out of three cardiovascular risk factors: hypertension, diabetes, current smoking.
4. Patients age 18-90 years.
5. Life expectancy of over 12 months.
6. WHO performance status of 0-2
7. Subject is able and has agreed to sign a consent form.

Exclusion Criteria:

1. Prior use of ADT in past 6 months prior to randomization. We will, however, allow prior use of anti-androgens such as Casodex, Chimax, Drogenil, and Cyprostat.
2. Known allergic reaction to Degarelix.
3. Any psychological, familial, sociological or geographical situation potentially hampering compliance with the study protocol and follow-up schedule.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Degarelix; GnRH Antagonist	Drug: Degarelix; Treatment will start with two injections of 120 mg each followed by maintenance of a single injection of 80 mg administered every 28 days; Other Names: Firmagon
ACTIVE_COMPARATOR: GnRH-agonist; GnRH Agonist	Drug: GnRH agonist; GnRH agonist at the discretion of the treating Urologist/Oncologist for 1 year

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
time to first cardiovascular event	To compare time to first cardiovascular event as estimated by the cumulated probability at the 1-year time-point of patients with advanced prostate cancer treated for one year with Degarelix vs. GnRH agonist. This will be a composite outcome composed of: Death, CVA, MI, TIA, cardiac emergency room visits, heart catheterization.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
time to first MACCE event	To compare time to first MACCE event as estimated by the cumulated probability at the 1-year timepoint of patients with advanced prostate cancer treated with Degarelix vs. GnRH agonist and combination therapy. MACCE will be defined as: Death of any cause; MI; CVA; Percutaneous coronary intervention, (PCI) with stent insertion	1 year
cardiac echocardiography	To compare change in ejection fraction (EF) as measured by cardiac echocardiography of patients with advanced prostate cancer treated with Degarelix vs. GnRH agonist, at baseline, six-, nine- and twelve-months of combination treatment.	1 year
Hormonal Profile	To compare testosterone serum levels (ng/dL) of patients with advanced prostate cancer treated with Degarelix vs. GnRH agonist, at baseline, three-, six- and twelve-months of combination treatment.	1 year
NTproBNP levels	To compare levels of NTproBNP (pg/mL) in patients with advanced prostate cancer treated with Degarelix vs. GnRH agonist, at baseline, three-, six-, nine- and twelve-months of combination treatment.	1 year
Adverse events	To compare rate of other adverse events in patients with advanced prostate cancer treated with Degarelix vs GnRH agonist and combination therapy.	1 year
PSA levles	To compare PSA serum levels (ng/mL) of patients with advanced prostate cancer treated with Degarelix vs. GnRH agonist, at baseline, three-, six- nine- and twelve-months of combination treatment.	1 year
BMI	To compare changes in body mass index (BMI) in patients with advanced prostate cancer treated with Degarelix vs. GnRH agonist, at baseline, three-, six- and twelve-months of combination treatment.	1 year
Quality of life: FACT-P questionnaire	To compare the quality of life by self-reported FACT-P questionnaire, by patients with advanced prostate cancer treated with Degarelix vs. GnRH agonist, at baseline, three-, six- and twelve-months of combination treatment	1 year
Glucose profile	To compare glucose levels (mg/dL) in patients with advanced prostate cancer treated with Degarelix vs GnRH agonist, at baseline, three-, six- and twelve-months of combination treatment.	1 year
Cholesterol levles	To compare Cholesterol serum levels (mg/dL) of patients with advanced prostate cancer treated with Degarelix vs. GnRH agonist, at baseline, three-, six- nine- and twelve-months of combination treatment.	1 year

Collaborators and Investigators

• Sponsor: Rabin Medical Center
• Collaborators: Ferring Pharmaceuticals

Publications and helpful links

General Publications

• Zengerling F, Jakob JJ, Schmidt S, Meerpohl JJ, Blumle A, Schmucker C, Mayer B, Kunath F. Degarelix for treating advanced hormone-sensitive prostate cancer. Cochrane Database Syst Rev. 2021 Aug 5;8(8):CD012548. doi: 10.1002/14651858.CD012548.pub2.

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): January 17, 2020
• Primary Completion (ANTICIPATED): January 17, 2023
• Study Completion (ANTICIPATED): January 17, 2023

Study Registration Dates

• First Submitted: October 24, 2019
• First Submitted That Met QC Criteria: November 27, 2019
• First Posted (ACTUAL): December 2, 2019

Study Record Updates

• Last Update Posted (ACTUAL): December 2, 2019
• Last Update Submitted That Met QC Criteria: November 27, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms
• Other Study ID Numbers: 0670-19-RMC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No