A Phase II Neoadjuvant Study of Enzalutamide, Abiraterone Acetate, Dutasteride and Degarelix in Men With Localized Prostate Cancer Pre-prostatectomy

This study investigates the pathologic effects of the combination of enzalutamide, abiraterone acetate, dutasteride, and degarelix when given for 12 weeks prior to prostatectomy in men with localized prostate cancer.

Enzalutamide, an androgen receptor (AR) antagonist, blocks binding of testosterone to the AR as well as preventing nuclear translocation of the AR and DNA binding. Abiraterone acetate inhibits the CYP17 pathway, which is involved in the formation of androgens. Dutasteride is a 5-alpha-reductase inhibitor which blocks conversion of testosterone to dihydrotestosterone. Degarelix, a gonadotropin-releasing hormone (GnRH) antagonist, binds to GnRH receptors on the pituitary gland thus suppressing testosterone release from the testes.

Therefore it is hypothesized that the combination of enzalutamide, abiraterone acetate, dutasteride, and degarelix will result in near-complete AR inhibition and produce favorable pathologic changes after 12 weeks of therapy.

Study Overview

• Status: Withdrawn
• Conditions: Prostate Cancer; Localized Prostate Cancer
• Intervention / Treatment: Drug: Enzalutamide; Drug: Abiraterone acetate; Drug: Prednisone; Drug: Dutasteride; Drug: Degarelix

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Johns Hopkins Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. Willing and able to provide written informed consent.
2. Age ≥ 18 years
3. Eastern cooperative group (ECOG) performance status ≤2
4. Documented histologically confirmed adenocarcinoma of the prostate
5. Willing to undergo prostatectomy as primary treatment for localized prostate cancer
6. High risk prostate cancer (per NCCN criteria): Gleason score 8-10 or T3a or PSA > 20 ng/mL -Or- Very-high risk prostate cancer (per NCCN criteria): T3b -T4
7. Serum testosterone ≥150 ng/dL
8. Able to swallow the study drugs whole as tablets
9. Willing to take abiraterone acetate on an empty stomach (no food should be consumed at least two hours before and for one hour after dosing).
10. Willing to use a condom if having sex with a pregnant woman, or use a condom and another effective method of birth control if having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with abiraterone.

Exclusion Criteria:

1. Prior local therapy to treat prostate cancer (e.g. radical prostatectomy, radiation therapy, brachytherapy)
2. Prior use of enzalutamide or abiraterone acetate

3. Prior or ongoing systemic therapy for prostate cancer including, but not limited to:

   1. Hormonal therapy (e.g. leuprolide, goserelin, triptorelin, degarelix)
   2. CYP-17 inhibitors (e.g. ketoconazole)
   3. Antiandrogens (e.g. bicalutamide, nilutamide)
   4. Second generation antiandrogens (e.g. enzalutamide, ARN-509)
   5. Immunotherapy (e.g. sipuleucel-T, ipilimumab)
   6. Chemotherapy (e.g. docetaxel, cabazitaxel)
4. Evidence of serious and/or unstable pre-existing medical, psychiatric or other condition (including laboratory abnormalities) that could interfere with patient safety or provision of informed consent to participate in this study.
5. Any psychological, familial, sociological, or geographical condition that could potentially interfere with compliance with the study protocol and follow-up schedule.
6. Abnormal bone marrow function [absolute neutrophil count (ANC)<1500/mm3, platelet count <100,000/mm3, hemoglobin <9 g/dL]
7. Abnormal liver function (bilirubin, AST, ALT ≥ 3 x upper limit of normal)
8. Abnormal kidney function (serum creatinine ≥ 2 x upper limit of normal)
9. Abnormal cardiac function as manifested by NYHA (New York Heart Association) class III or IV heart failure or history of a prior myocardial infarction (MI) within the last five years prior to enrollment in the study.
10. History of prior cardiac arrhythmia.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of prostatectomy specimens with a complete response rate	Proportion of prostatectomy specimens with complete response rate after 12 weeks of therapy	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of prostatectomy specimens with a negative surgical margin rate	Proportion of prostatectomy specimens with a negative surgical margin rate after 12 weeks of therapy	12 weeks
Proportion of prostatectomy specimens with a near-pathologic complete response	Proportion of prostatectomy specimens with a near-pathologic complete response (<=5mm of residual tumor) after 12 weeks of therapy	12 weeks
Proportion of prostatectomy specimens with pathologic T3 disease	Proportion of prostatectomy specimens with pathologic T3 disease after 12 weeks of therapy	12 weeks
Change in immunologic parameters (TREC levels and antibody responses)	Change in immunologic parameters (TREC levels and antibody responses) after 12 weeks of enzalutamide, abiraterone acetate, dutasteride and degarelix and an additional month of degarelix monotherapy (16 weeks total).	16 weeks
Proportion of radiographic disappearance of MRI detectable significant prostate nodules	Proportion of radiographic disappearance of MRI detectable significant prostate nodules after 12 weeks of therapy.	12 weeks
Proportion of men who receive adjuvant radiation therapy within 1 year of prostatectomy	Proportion of men who receive adjuvant radiation therapy within 1 year of prostatectomy (12 weeks of therapy + 1 year = 64 weeks)	64 weeks
PSA progression free survival	The biochemical (i.e. PSA) progression free survival estimate two years after the last patient has accrued.	2 years after last accrual
Overall survival	The overall survival estimate two years after the last patient has accrued.	2 years after last accrual
Incidence and severity of adverse events	Safety as assessed by the incidence and severity of adverse events and serious adverse events graded according to the National Cancer Institute - Common Terminology Criteria for adverse events (CTCAE) version 4.0	16 weeks
Exploratory biomarkers assessment	Exploratory biomarker Assessment. Examples of these may include, but are not limited to: assessment for genomic PTEN loss via fluorescence in situ hybridization (FISH), PTEN immunohistochemistry (IHC), assessment for alteration in MYC/chromosome 8q24 via FISH, RNAseq analysis, serum drug/androgen levels and intraprostatic drug/androgen levels.	16 weeks

Collaborators and Investigators

• Sponsor: Kenneth Pienta, MD
• Collaborators: Prostate Cancer Foundation Norway
• Investigators: Principal Investigator: Kenneth J Pienta, MD, Johns Hopkins University

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (Actual): January 1, 2015
• Study Completion (Actual): January 1, 2015

Study Registration Dates

• First Submitted: June 6, 2014
• First Submitted That Met QC Criteria: June 6, 2014
• First Posted (Estimate): June 10, 2014

Study Record Updates

• Last Update Posted (Estimate): January 26, 2015
• Last Update Submitted That Met QC Criteria: January 22, 2015
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Keywords: prostate cancer; prostatectomy; localized prostate cancer
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Steroid Synthesis Inhibitors; 5-alpha Reductase Inhibitors; Prednisone; Abiraterone Acetate; Dutasteride
• Other Study ID Numbers: Neoadj enz/abi/dut/deg