Clinical trial NCT02268175: Enzalutamide/Leuprolide +/- Abiraterone/Pred in Prostate
Official title: A Phase II Randomized Study of Enzalutamide+Leuprolide Versus Enzalutamide+Leuprolide+Abiraterone Acetate+Prednisone as Neoadjuvant Therapy for HIgh-Risk Prostate Cancer Undergoing Prostatectomy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Prostate Adenocarcinoma
Prostate Cancer
High Risk Prostate Cancer
Keywords: prostate adenocarcinoma
advanced prostate cancer
high risk prostate cancer
Lead sponsor: Dana-Farber Cancer Institute
Sponsor class: OTHER
Collaborators: name: Medivation, Inc.
First posted: 2014-10-20
Enrollment: 75
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study is comparing the effectiveness of enzalutamide with or without abiraterone acetate for men with high-risk, localized prostate cancer.

Detailed description: In this research study, the investigators are comparing the effectiveness of enzalutamide with or without abiraterone acetate for men with high-risk, localized prostate cancer.

Abiraterone acetate with prednisone and enzalutamide are currently FDA-approved for use in the treatment of patients with metastatic castration-resistant prostate cancer, however they are investigational for the treatment of localized prostate cancer. Abiraterone acetate works by decreasing the production of male sex hormones, which cause prostate cancer growth. Enzalutamide works by blocking the effects of male sex hormones, which cause prostate cancer growth.

The FDA (the U.S. Food and Drug Administration) has not approved the combination of enzalutamide and abiraterone acetate as neoadjuvant therapy for high risk prostate cancer undergoing prostatectomy but each drug has been approved for the treatment of more advanced prostate cancer.

Participants will be randomized to one of two study arms. Randomization means that the participant is put into a group by chance. It is like flipping a coin. Neither participant nor the research doctor will choose what group participants are randomized to.

The names of the study medications involved in this study are:

* Enzalutamide
* Abiraterone Acetate
* Prednisone
* Leuprolide Acetate

Eligibility criteria: Inclusion Criteria:

* Male greater than or equal 18 years of age.
* Histologically confirmed adenocarcinoma of the prostate without histological variants (including overt neuroendocrine differentiation, small cell neuroendocrine carcinoma features, sarcomatoid features, pure ductal adenocarcinoma, squamous or transitional cell carcinoma).
* Must have tissue available from the pre-treatment diagnostic biopsy (tissue blocks if possible; if not possible, 10 unstained slides from each positive core sample for a total of 30 slides).
* Must have three core biopsies involved with cancer (a minimum of 6 core biopsies must be obtained). Prostate biopsy must be within three months from screening.
* Participants must have the following features:

  * Intermediate-risk disease defined as Gleason 4+3=7 disease OR
  * High-risk disease defined as Gleason 8-10 OR PSA \> 20 ng/dL OR T3 disease (by prostate MRI)
* No evidence of metastatic or nodal disease as determined by radionuclide bone scans CT/MRI.
* Participants must be candidates for RP and considered surgically resectable by urologic evaluation.
* ECOG performance status 0 to 1 (Appendix A).
* Participants must have normal organ and marrow function as defined below:

  * WBC ≥ 3,000/mcL
  * ANC ≥ 1,500/mcL
  * Platelets ≥ 100,000/mcL
  * Serum potassium ≥ 3.5 mmol/L
  * AST, ALT, and total bilirubin ≤ 1.5 x Institutional ULN
  * Calculated creatinine clearance ≥ 60 mL/min
  * PTT ≤ 60, INR ≤ 1.5 x Institutional ULN unless on warfarin therapy (investigator would need to determine if safe for participant to stop warfarin prior to biopsy and warfarin therapy)
  * Controlled blood pressure defined as a systolic blood pressure ≤ 140 mmHg and diastolic blood pressure ≤ 90 mmHg on no more than three anti-hypertensive agents. Drug formulations containing two or more anti-hypertensive agents will be counted based on the number of active agents in each formulation.

Exclusion Criteria:

* Prior hormone therapy for prostate cancer including orchiectomy, antiandrogens (including first-generation antiandrogens, enzalutamide, ARN-509 and others), CYP17 inhibitors (including abiraterone, TAK-700, galeterone, ketoconazole, and others), estrogens, LHRH agonist/antagonists. Prior therapy with 5α-reductace inhibitors is allowed. LHRH therapy allowed if begun within 4 weeks of day 1.
* Prior chemotherapy, radiation therapy, or immunotherapy for prostate cancer.
* Prior systemic treatment with an azole drug within four weeks of screening visit.
* Hypogonadism or severe androgen deficiency as defined by screening serum testosterone \< 200 ng/dL.
* Clinically significant cardiovascular disease including:
* Acute coronary syndrome within 6 months of screening visit;

  * Hypotension defined as a systolic blood pressure \< 86 mmHg;
  * Bradycardia defined as a heart rate of \< 50 beats per minute, unless pharmaceutically induced and thus reversible (i.e. beta blockers);
  * Uncontrolled angina (requiring escalating doses of nitrates) within 3 months of screening visit;
  * Congestive heart failure NYHA Class III or IV or subjects with a history of congestive heart failure NYHA Class III or IV, unless screening ECHO results in left ventricular ejection fraction that ≥ 45%;
  * History of clinically significant ventricular arrhythmias (e.g. ventricular tachycardia, ventricular fibrillation, torsades de pointes);
  * Prolonged corrected QT interval by the Fridericia correction formula (QTcF) on screening EKG \> 470 msec;
  * History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place;
* History of seizure or any condition or concurrent medication that may predispose to seizure.
* Thromboembolism within 6 months of screening visit.
* Severe hepatic impairment (Child-Pugh Class C).
* Active or symptomatic viral hepatitis or chronic liver disease.
* History of pituitary or adrenal dysfunction.
* GI disorders which may interfere with the absorption of the study drug.
* Pre-existing condition that warrants long-term corticosteroid use.
* Concomitant use of medications that may alter pharmacokinetics of abiraterone or enzalutamide.
* Individuals with a history of a different malignancy are ineligible except for the following circumstances: 1) individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy, or 2) individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: non-muscle invasive bladder cancer, basal cell or squamous cell carcinoma of the skin.
* Major surgery or radiation therapy within 30 days of screening.

Primary outcomes:
measure: Percentage of Participants With Pathologic Complete Response (pCR) or Minimal Residual Disease (MRD)
timeFrame: after RP approximately 24 weeks from study entry
Secondary outcomes:
measure: Participants With Pathologic Complete Response (pCR)
timeFrame: after RP approximately 24 weeks from study entry
measure: Residual Cancer Burden (RCB)
timeFrame: after RP approximately 24 weeks from study entry
measure: Positive Surgical Margin Status
timeFrame: after RP approximately 24 weeks from study entry
measure: Median Prostate Specific Antigen (PSA) Nadir
timeFrame: PSA was assessed at baseline and every cycle during neoadjuvant therapy (up to 24 weeks).
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Seattle
country: United States
facility: University of Washington
state: Washington
Study officials:
affiliation: Dana-Farber Cancer Institute
name: Mary-Ellen Taplin, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: McKay RR, Ye H, Xie W, Lis R, Calagua C, Zhang Z, Trinh QD, Chang SL, Harshman LC, Ross AE, Pienta KJ, Lin DW, Ellis WJ, Montgomery B, Chang P, Wagner AA, Bubley GJ, Kibel AS, Taplin ME. Evaluation of Intense Androgen Deprivation Before Prostatectomy: A Randomized Phase II Trial of Enzalutamide and Leuprolide With or Without Abiraterone. J Clin Oncol. 2019 Apr 10;37(11):923-931. doi: 10.1200/JCO.18.01777. Epub 2019 Feb 27.