Trial of Radiotherapy With Leuprolide and Enzalutamide in High Risk Prostate Cancer

Phase II Trial of Definitive Radiotherapy With Leuprolide and Enzalutamide in High Risk Prostate Cancer

This phase II trial studies the safety of giving enzalutamide with leuprolide acetate before and after radiation therapy and to see how well it works in treating patients with prostate cancer that is at high risk of returning. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Most types of prostate cancer also need testosterone to grow and spread. After radiation therapy, patients often receive treatments to reduce testosterone to prevent the cancer from returning. Leuprolide acetate works by reducing the amount of testosterone that the body makes. Enzalutamide is a stronger treatment that may block testosterone from reaching cancer cells. Adding enzalutamide to treatment with leuprolide acetate after radiation therapy may help prevent high-risk prostate cancer from returning and improve patient survival.

PRIMARY OBJECTIVES:

I. To determine the feasibility and safety of the combination of enzalutamide and leuprolide acetate (leuprolide) in patients undergoing definitive radiation therapy for high-risk prostate cancer or with pelvic nodal involvement.

II. To determine the prostate-specific antigen (PSA) complete response rate with the combination of enzalutamide and leuprolide (PSA-complete response (CR) as determined by PSA nadir =< 0.3) in patients undergoing radiation therapy for high-risk prostate cancer or pelvic nodal involvement.

SECONDARY OBJECTIVES:

I. To determine time to biochemical failure as determined by the American Society for Radiation Oncology (ASTRO) Phoenix definition of nadir + 2 ng/mL, local progression, regional progression, and distant metastases.

II. To determine time to clinical progression free survival III. To assess changes in PSA nadir and PSA and testosterone levels. IV. To assess changes in hemoglobin A1c (HbA1c), fasting glucose, fasting insulin and fasting lipid and cholesterol levels.

V. To document changes in quality of life outcomes.

EXPLORATORY OBJECTIVES:

I. To identify potential mutations and changes gene copy number associated with enzalutamide resistance in patients with high risk prostate cancer.

II. To identify gene expression patterns, splice variants, and gene signatures associated with enzalutamide treatment and enzalutamide resistance in patients with high risk prostate cancer.

III. To identify changes in the immune response with enzalutamide treatment.

OUTLINE:

Patients receive enzalutamide orally (PO) once daily (QD) and leuprolide acetate intramuscularly (IM) every 1, 3, 4, or 6 months for 24 months. Patients also undergo standard of care intensity-modulated radiation therapy (IMRT) 5 days per week for 5 weeks beginning at week 8, followed by optional brachytherapy. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 6 weeks, 3-4 months, 6, 12, 18, 24, and 36 months.

Inclusion Criteria:

1. Histologically confirmed diagnosis of adenocarcinoma of the prostate within 180 days prior to registration at very high risk of recurrence as determined by 2 or more of the following combinations:

   • cT3a/b
   • PSA ≥20
   • Gleason score 8-10
   • ≥33% core involvement OR any patient with pelvic lymph node involvement ≥1cm as determined by pelvic CT or MRI imaging will meet eligibility criteria for enrollment.

2. Standard staging exams for patients with high-risk prostate cancer including bone scan or NaF Positron Emission Tomography (PET) /CT scan, and pelvic and prostate MRI.

3. No distant metastases (M0) on bone scan or NaF PET/CT within 90 days prior to registration. Equivocal bone scan findings are allowed if the physician determines that distant metastases are unlikely based on clinical judgment.

4. Zubrod Performance Status 0-2 within 60 days prior to enrollment.

5. Age ≥18

6. Complete blood count (CBC) with differential obtained within 30 days prior to registration on study, with adequate bone marrow function defined as follows:

   1. Absolute neutrophil count (ANC) ≥1,800 cells/mm3
   2. Platelets ≥100,000 cells/mm3
   3. Hemoglobin ≥8.0 g/dl (The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable)
   4. Serum creatinine <2.0 mg/dl and creatinine clearance >40 mL/min within 30 days prior to registration
   5. Bilirubin <1.5 x ULN and Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) <2 × ULN within 21 days prior to registration

7. Patients, even if surgically sterilized (i.e., status post vasectomy), who:

   1. 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, or
   2. Agree to completely abstain from intercourse

8. Patient must be able to provide study-specific informed consent prior to study entry.

Exclusion Criteria:

1. Definite evidence of metastatic disease

2. Prior radical prostatectomy or bilateral orchiectomy for any reason

3. Prior invasive malignancy (except non-melanoma skin cancer) unless disease-free or not requiring systemic therapy for a minimum of 3 years.

4. Prior systemic chemotherapy for prostate cancer (Note that prior chemotherapy for a different cancer is allowed).

5. Prior radiotherapy, including brachytherapy, to the region of the prostate that would result in overlap of radiation therapy fields.

6. Previous hormonal therapy such as LHRH agonists (e.g. goserelin, leuprolide), anti-androgens (e.g. flutamide, bicalutamide), estrogens (e.g. DES), or surgical castration (orchiectomy)

7. Known hypersensitivity to enzalutamide or related compounds

8. History of adrenal insufficiency

9. Patients who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.

10. Prior allergic reaction to the drugs involved in this protocol.

11. Cushing's syndrome

12. Severe chronic renal disease (serum creatinine >2.0 mg/dl and confirmed by creatinine clearance <40 mL/minute)

13. Chronic liver disease (bilirubin >1.5x ULN, ALT or AST >2x ULN)

14. Active/Uncontrolled Viral Hepatitis

15. Chronic treatment with glucocorticoids within one year.

16. History of seizure including febrile seizure or any condition that may predispose to seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss of consciousness requiring hospitalization). Also, current or prior treatment with antiepileptic medications for the treatment of seizures or history of loss of consciousness or transient ischemic attack within 12 months prior to randomization.

17. Clinically significant cardiovascular disease including:

    1. Myocardial infarction within 6 months prior to screening
    2. Uncontrolled angina within 3 months prior to screening
    3. Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subjects with history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multigated acquisition (MUGA) scan performed within 3 months results in a left ventricular ejection fraction that is ≥45%;
    4. History of clinically significant ventricular arrhythmias (e.g. ventricular tachycardia, ventricular fibrillation, torsades de pointes);
    5. History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place;
    6. Uncontrolled hypertension as indicated by a resting systolic blood pressure >170 mm Hg or diastolic blood pressure >105 mm Hg at screening. Patients with initially elevated systolic blood pressure >170 mm Hg or diastolic blood pressure >105 mm Hg are eligible if they undergo medical management and are re-screened.