Denosumab Plus Enzalutamide, Abiraterone and Prednisone Compared to Denosumab Plus Enzalutamide Alone for Men With Castrate Resistant Prostate Cancer (CRPC) With Bone Metastases

Phase 2

Terminated

Interventions: Biological: Denosumab
Drug: Enzalutamide
Drug: Abiraterone
Drug: Prednisone

Brief Summary: This is a correlative study to characterize serum metabolites associated with bone deposition, growth and turnover in patients with newly diagnosed metastatic CRPC who are not currently receiving bone targeting agents.

Recruitment & Eligibility

Inclusion Criteria

Histologic proof of adenocarcinoma of the prostate with clinical evidence of metastatic disease to the bone.
Castrate resistant progression of prostate carcinoma, as shown by:
- Serum testosterone level <50 ng/dL or prior bilateral orchiectomy. Treatment to maintain castrate levels of testosterone should continue, and
  - Either symptomatic progression, or, if patient is asymptomatic then a rising serum PSA in two occasions at least 1 week apart, with minimum pre-treatment serum PSA of 5 ng/dL.
Patients with nodal disease are eligible.
Bi-dimensionally measurable disease within the bone.
Life expectancy of at least 12 weeks.
ECOG Performance status < 2
Adequate:
- Bone marrow function; absolute neutrophil count > 1,500 mm3, platelet count of > 100,000 mm3 and hemoglobin > 9.0 gm/dl.
- Hepatic function; SGOT/SGPT and conjugated bilirubin less than twice the upper limit of normal.
- Renal function; serum creatinine ≤ 2 mg/dL (or, if creatinine > 2 mg/dL, then a creatinine clearance of at least 35 ml/min (measured or estimated by the Cockroft formula:

CLcr = [(140-age) x wt (kg)]/[72 x serum creatinine (mg/dL)].

No evidence of coagulopathy as indicated by PT < 1.5X upper limit of normal.
Serum calcium (corrected) from 8 to11.5 mg/dL (2 to 2.9 mmol/L) - Patients must sign an informed consent indicating that they are aware of the investigational nature of the study.

Exclusion Criteria

Patients with variant histologies (e.g., ductal or small cell carcinoma).
Patients with visceral disease are ineligible.
Patients who have had prior Sipuleucel-T, docetaxel, cabazitaxel, abiraterone or enzalutamide as a single agent, or in combination therapy.
Concurrent cancer chemotherapy, radiotherapy or surgery.
Concurrent serious infection.
Life threatening illness (e.g., congestive heart failure, uncontrolled angina or myocardial infarction in the prior six months).
Hypertension uncontrolled by medication.
Patients who are known to require invasive dental procedures.
No known or suspected brain metastases (NOTE: patients with treated epidural disease are allowed)
Administration of any investigational drug within 28 days prior to receipt of denosumab.
Age ≤ 18 years of age

Arm && Interventions

Group	Intervention	Description
Standard of Care	Denosumab	Denosumab plus enzalutamide alone
Alliance A031201	Denosumab	Denosumab plus enzalutamide, abiraterone and prednisone
Alliance A031201	Enzalutamide	Denosumab plus enzalutamide, abiraterone and prednisone
Alliance A031201	Abiraterone	Denosumab plus enzalutamide, abiraterone and prednisone
Alliance A031201	Prednisone	Denosumab plus enzalutamide, abiraterone and prednisone
Standard of Care	Enzalutamide	Denosumab plus enzalutamide alone

Primary Outcome Measures

Name	Time	Method
Measure Change in Serum-based Metabolites Associated With Bone Deposition, Growth and Turnover in Patients Who Have CRPC With Clinical Evidence of Metastatic Disease to the Bone, All Using Gas Chromatography-time-of-flight Mass Spectrometry (GC-TOFMS).	Prior to Registration, Registration, Day 1 of cycle 4 and 13

Secondary Outcome Measures

Name	Time	Method
Measure Time (Months) to Duration of Response of Patients on Therapy.	Day 1 of each S.O.C cycle (28 days), and until confirmed radiographic disease progression AND initiation of other standard OR investigational agents for prostate cancer, up to 5 years post treatment
Measure Time (Months) to Skeletal Related Event (SRE) of Patients on Therapy	Day 1 of each S.O.C cycle (28 days), and until confirmed radiographic disease progression AND initiation of other standard OR investigational agents for prostate cancer, up to 5 years post treatment
Measure Time (Months) to Progression-free Survival of Patients on Therapy	Day 1 of each S.O.C cycle (28 days), and until confirmed radiographic disease progression AND initiation of other standard OR investigational agents for prostate cancer, up to 5 years post treatment