A031201: PHASE III TRIAL OF ENZALUTAMIDE (NSC # 766085) VERSUS ENZALUTAMIDE, ABIRATERONE AND PREDNISONE FOR CASTRATION RESISTANT METASTATIC PROSTATE CANCER

Summary

arm a: enzalutamide alone
Patients randomized to arm a will be instructed to take 160 mg enzalutamide by mouth
daily.

Study drug doses should be taken as close as possible to the same time each day. Study
patients will take four capsules of enzalutamide once daily. enzalutamide can be taken with or
without food.

if dosing is missed on one day for any reason, double dosing should noT occur the following
day.

inducers and inhibitors of (cytochrome) CYP (CYPs are the major enzymes involved in drug metabolism and bioactivation) enzymes: in vitro drug metabolism studies suggest that enzalutamide may have the potential to induce cytochrome CYP3a4 and to inhibit cytochrome CYP1a2, cytochrome CYP2B6, cytochrome CYP2C8, cytochrome CYP2C9, cytochrome CYP2C19, cytochrome CYP2D6, and cytochrome CYP3a4/5; therefore, concomitant medications that are substrates of any of these enzymes should be used with caution, and relevant monitoring should be considered, especially for substrates known to cause seizure, because the possibility of drug-drug interactions cannot be fully excluded. Since the metabolism of enzalutamide is not known, caution should be taken for the concomitant use of strong inhibitors and inducers of CYP enzymes and alternative products used when available.

arm B: enzalutamide, abiraterone, and prednisone
Patients assigned to arm B should start all components of the regimen: abiraterone, prednisone, and enzalutamide on the same day. Per Section 5.1.2, patients are required to secure their own supply of the abiraterone. arrangements with third party insurers, private or public, should be made prior to registration/randomization.

if dosing of enzalutamide, abiraterone, and/or prednisone is missed on one day for any reason, double dosing should noT occur the following day.

inducers and inhibitors of CYP enzymes: in addition to the information above regarding the interaction of CYP enzymes and enzalutamide, abiraterone is an inhibitor of the hepatic drug-metabolizing enzyme cytochrome CYP2D6. avoid co-administration with cytochrome CYP2D6 substrates that have a narrow therapeutic index. if an alternative cannot be used, exercise caution and consider a dose reduction of the cytochrome CYP2D6 substrate. additionally, abiraterone is a substrate of cytochrome CYP3a4 in vitro. Strong inhibitors and inducers of cytochrome CYP3a4 should be avoided or used with caution.

Participant Eligibility


* Must have progressive CRPC with histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features.

* Must have measurable or non-measurable disease as defined by the protocol.

* Patients must have progressive disease at study entry defined as one or more of the following three criteria that occurred while the patient was on androgen deprivation therapy. For patients enrolling on the basis of soft tissue or bone progression, the baseline scan must show progression relative to a comparison scan. If the comparison scan is not available, the baseline scan report must reference the previous scan to document progression.
(1) PSA progression defined by minimum of two rising PSA levels with an interval of >1 week between each determination, (2) soft tissue disease progression defined by RECIST 1.1, (3) bone disease progression defined by PCWG2 with two or more new lesions on bone scan.

* Must be >18 years of age and have ECOG performance status of 0-1.

* Must be asymptomatic (score of 0-1 on BPI-SF question #3) or mildly symptomatic (score
of 2-3 on BPI-SF question #3) from prostate cancer.

* Must not have had prior treatment with taxane-based chemotherapy for metastatic disease.
o Patients with prior taxane-based chemo as neoadjuvant or adjuvant therapy for local disease or in the PSA clinical state are eligible if the total duration of exposure was
< 6 cycles and chemo was completed > 6 months prior to registration.
o Patients with prior taxane-based chemo received for 1 cycle are eligible if the treatment ended due to allergic reactions or intolerance.

* Patients receiving bisphosphonate therapy or denosumab must be on a stable dose for at least 4 weeks prior to enrollment.

* Patients must maintain ongoing androgen deprivation therapy with a GnRH analogue, antagonist, or bilateral orchiectomy.
-Required Initial Laboratory Values:
-Granulocytes >= 1,500/[MICRO-SYMBOL]L
-Platelet count >= 100,000/[MICRO-SYMBOL]L
-Hemoglobin >= 9 g/dL
-Creatinine <= 2 x upper limits of normal (ULN)
-Bilirubin <= 1.5 x ULN
-AST or ALT <= 2 x ULN
-Albumin > 3 g/dl
-Testosterone <= 50 ng/dL (1.7 nmol/L)