Hormone Therapy, Radiation Therapy, and Steroid 17alpha-monooxygenase TAK-700 in Treating Patients With High-Risk Prostate Cancer

OBJECTIVES:

Primary

- To evaluate the difference in overall survival of patients with clinically localized
prostate cancer with unfavorable prognostic features between a) standard treatment
(androgen-deprivation therapy [ADT] + radiotherapy) and b) standard treatment with the
addition of 24 months of steroid 17alpha-monooxygenase TAK-700 (TAK-700).

Secondary

- To characterize differences between the treatment groups with respect to incidence of
unexpected grade ≥ 3 adverse events and/or clinically significant decrement in
patient-reported quality of life (QOL) among subjects treated with TAK-700.

- To compare rates and cumulative incidence of biochemical control (freedom from PSA
failure), local/regional progression, and distant metastases.

- To compare rate and cumulative incidence of clinical failure, defined as
prostate-specific antigen (PSA) > 25 ng/mL, documented local disease progression,
regional or distant metastasis, or initiation of ADT.

- To compare prostate cancer-specific survival and other-cause mortality.

- To compare the change in severity of fatigue as measured by the Patient-Reported Outcome
Measurement Information System (PROMIS) fatigue short form.

- To compare changes in patient-reported QOL as measured by Expanded Prostate Cancer Index
Composite (EPIC).

- To assess quality-adjusted survival using the EQ-5D.

- To compare nadir and average serum testosterone at 12 and 24 months during treatment.

- To compare changes in hemoglobin A1C, fasting glucose, and fasting insulin during 24
months of systemic treatment and during the first three years of follow-up.

- To compare changes in fasting lipid levels during 24 months of treatment and during the
first three years of follow-up.

- To compare changes in body mass index (BMI) during 24 months of treatment and during the
first three years of follow-up.

- To compare the incidence of adverse events ascertained via CTCAE version 4.

- To compare the rate of recovery of testosterone to > 230 ng/dL (accepted threshold for
supplementation) after 12 and 24 months of follow-up.

- To compare the median time to recovery of testosterone to > 230 ng/dL during the first
five years of follow-up.

- To assess cumulative incidence of relevant clinical survivorship endpoints including new
diagnosis of type 2 diabetes, coronary artery disease, myocardial infarction, stroke,
pulmonary embolism, deep vein thrombosis, or osteoporotic fracture.

OUTLINE: This is a multicenter, randomized study. Patients are stratified according to risk
group (see Disease Characteristics) and type of radiation therapy (RT) boost
(intensity-modulated RT (IMRT) vs brachytherapy). Patients are randomized to 1 of 2 treatment
arms.

- Arm I: Patients receive standard androgen suppression (AS) with a luteinizing
hormone-releasing hormone (LHRH) agonist (such as leuprolide, goserelin, buserelin, or
triptorelin) for 24 months from initiation and oral (PO) antiandrogen (such as flutamide
or bicalutamide) beginning 2 months prior and for the duration of radiation therapy
(RT).

- Arm II: Patients receive the same standard AS with LHRH agonist and oral antiandrogen as
in arm 1. Patients also receive steroid 17alpha-monooxygenase TAK-700 (TAK-700) PO twice
daily (BID) for 2 years.

In both arms, patients undergo IMRT or 3D-conformal RT to the whole pelvis once daily, 5 days
a week, for 6-8 weeks. Some patients also receive brachytherapy.

Quality of life is assessed via the Patient-Reported Outcome Measurement Information System
(PROMIS) Fatigue Scale, the Expanded Prostate Cancer Index Composite (EPIC-26), and the
EuroQol (EQ-5D) assessments at baseline and periodically during the study.

Serum may be collected from some patients for correlative studies.

After completion of study therapy, patients are followed every 3 months for 2 years, every 6
months for 1 year, and then annually thereafter.

DISEASE CHARACTERISTICS:

- Histologically confirmed diagnosis of adenocarcinoma of the prostate within 180 days
prior to registration at high risk for recurrence as determined by one of the
following combinations (risk group):

- Gleason Score (GS) ≥ 9, PSA ≤ 150 ng/mL, any T stage

- GS ≥ 8, PSA < 20 ng/mL, T stage ≥ T2

- GS ≥ 8, PSA ≥ 20-150 ng/mL, any T stage

- GS ≥ 7, PSA ≥ 20-150 ng/mL, any T stage

- Baseline serum PSA value performed with an FDA-approved assay (e.g., Abbott,
Hybritech), obtained prior to any luteinizing hormone-releasing hormone (LHRH) agonist
or antiandrogen therapy, within 180 days of randomization

- Androgen deprivation therapy (ADT), such as LHRH agonists (e.g., goserelin,
leuprolide), anti-androgens (e.g., flutamide, bicalutamide), estrogens (e.g., diethyl-
stilbestrol [DES]), or surgical castration (orchiectomy), may have been started prior
to registration, provided that registration is within 50 days of beginning ADT; please
note: if the patient has started ADT he will not be eligible to participate in the
quality of life component of this study

- Clinically negative lymph nodes as established by imaging (abdominal and/or pelvic CT
or abdominal and/or pelvic MRI), nodal sampling, or dissection within 90 days prior to
registration

- Patients with lymph nodes equivocal or questionable by imaging are eligible if
the nodes are < 2.0 cm

- No distant metastases (M0) on bone scan within 90 days prior to registration

- Equivocal bone scan findings are allowed if plain films are negative for
metastasis

- No definite evidence of metastatic disease

- Any patient undergoing brachytherapy must have transrectal ultrasound confirmation of
prostate volume < 60 cc, American Urological Association (AUA) score ≤ 15 within 60
days of registration, and no history of prior transurethral resection of the prostate
(TURP)

- Prior TURP is permitted for patients who receive external-beam radiotherapy
(EBRT) only

PATIENT CHARACTERISTICS:

- Height, weight, Zubrod performance status 0-1

- Absolute neutrophil count (ANC) ≥ 1,800 cells/mm^3

- Platelets ≥ 100,000 cells/mm^3

- Hemoglobin ≥ 8.0 g/dL (The use of transfusion or other intervention to achieve Hgb ≥
8.0 g/dL is acceptable)

- Serum creatinine < 2.0 mg/dL

- Creatinine clearance > 40 mL/minute

- Bilirubin < 1.5 x upper limit of normal (ULN)

- Alanine aminotranserase (ALT) or aspartate aminotransferase (AST) < 2.5 x ULN

- No PSA > 150 ng/mL

- Screening calculated ejection fraction ≥ ULN by multiple-gated acquisition (MUGA) scan
or by echocardiogram

- Androgen deprivation therapy (ADT), such as LHRH agonists (e.g., goserelin,
leuprolide), anti-androgens (e.g., flutamide, bicalutamide), estrogens (e.g., DES), or
surgical castration (orchiectomy) may have been started prior to registration,
provided that registration is within 50 days of beginning ADT.

- Patients, even if surgically sterilized (i.e., status post vasectomy), must agree to
practice effective barrier contraception during the entire study treatment period and
for 4 months (120 days) after the last dose of study drug

- No prior invasive malignancy (except non-melanoma skin cancer) unless disease-free or
not requiring systemic therapy for a minimum of 3 years

- No known hypersensitivity to TAK-700 or related compounds

- No history of adrenal insufficiency

- No history of myocardial infarction, unstable symptomatic ischemic heart disease,
ongoing arrhythmias of grade > 2 (NCI CTCAE, version 4.02) thromboembolic events
(e.g., deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular
events), or any other cardiac condition (e.g., pericardial effusion restrictive
cardiomyopathy) within 6 months prior to registration

- Chronic stable atrial fibrillation on stable anticoagulant therapy is allowed

- No New York Heart Association Class III or IV heart failure

- No ECG abnormalities of Q-wave infarction, unless identified 6 or more months prior to
screening, or corrected QT (QTc) interval > 460 msec

- No prior allergic reaction to the drugs involved in this protocol

- No Cushing syndrome

- No severe chronic renal disease or chronic liver disease

- No uncontrolled hypertension despite appropriate medical therapy within 21 days prior
to registration (blood pressure of greater than 150 mm Hg systolic and 90 mm Hg
diastolic at 2 separate measurements no more than 60 minutes apart during screening
visit)

- No serious infection within 14 days prior to registration

- No uncontrolled nausea, vomiting, or diarrhea (CTCAE grade ≥ 3) despite appropriate
medical therapy at the time of registration

- No known gastrointestinal (GI) disease or GI procedure that could interfere with the
oral absorption or tolerance of TAK-700, including difficulty swallowing tablets

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Prior testosterone administration is allowed if last administered at least 90 days
prior to registration

- No prior radical prostatectomy, cryosurgery for prostate cancer, or bilateral
orchiectomy for any reason

- No prior systemic chemotherapy for prostate cancer

- Prior chemotherapy for a different cancer is allowed

- No prior radiotherapy, including brachytherapy, to the region of the prostate that
would result in overlap of radiation therapy fields

- No previous hormonal therapy for > 50 days

- No chronic treatment with glucocorticoids within one year

- No major surgery within 14 days prior to registration

- No other investigational agent

- No other anticancer therapy

- No concurrent hormonal therapies including estrogens or herbal products

- No concurrent ketoconazole or aminoglutethimide

- No chronic use of systemic corticosteroids, such as oral prednisone