Abiraterone, Radiotherapy and Short-Term Androgen Deprivation in Unfavorable Localized Prostate Cancer

Study Overview
=================
Brief Summary
-----------------
The addition of abiraterone acetate to standard treatment of radiotherapy and short-term androgen deprivation will increase the frequency of undetectable PSA.

Detailed Description
-----------------
This is a single arm two-site study of 37 men with unfavorable prostate cancer (defined as having a single high risk factor). Patients will concurrently initiate 6 months of standard-of-care GNRH agonist therapy and once daily abiraterone acetate/prednisone. After 2 months of lead-in hormonal treatment, definitive standard-of-care prostate/seminal vesicle radiotherapy will be delivered, to a total dose of 75-80 Gy.

Official Title
-----------------
A Phase II Trial of Abiraterone Acetate, Radiotherapy and Short-Term Androgen Deprivation in Men With Unfavorable Risk Localized Prostate Cancer

Conditions
-----------------
Prostate Cancer

Intervention / Treatment
-----------------
* Drug: Abiraterone acetate
* Drug: Androgen deprivation
* Radiation: Radiation Therapy
* Drug: Prednisone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: One of the following high risk criteria: Gleason Score 7 with PSA ≤ 20 ng/ml and clinical T1-2, or Gleason Score 8-10, PSA ≤ 20 ng/ml and clinical T1-2a, or PSA 10.1-40 ng/ml with GS < 7 and clinical T1-2, or Clinical T3 with Gleason Score < 7 and PSA ≤ 10 ng/ml. ECOG Performance Status ≤ 1 Digital rectal exam within 90 days of registration on study CBC with differential with adequate bone marrow function defined as follows: Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3, Platelets > 100,000/µL and Hemoglobin ≥ 9g/dL Serum potassium ≥ 3.5 mEq/L Serum albumin > 3.0 g/dl Total bilirubin < 1.5 X of institutional upper limit of normal (ULN) AST(SGOT)/ALT(SGPT) < 1.5 X ULN Calculated creatinine clearance > 60 mL/min Age > 18 years Able to swallow a whole tablet and take abiraterone acetate on an empty stomach (defined as no food for two hours before and one hour after abiraterone acetate ingestion) Ability to understand and sign a written informed consent document Written authorization for use and release of health and research study information has been obtained Be willing/able to adhere to the prohibitions and restrictions specified in this protocol Subjects who have partners of childbearing potential must be willing to use a method of birth control with adequate barrier protections as determined acceptable by the principal investigator during the study and for 1 week after the last dose of abiraterone acetate. Exclusion Criteria: Bone, visceral or soft tissue metastasis, including lymph nodes (>2 cm in longest diameter) Prior therapy for prostate cancer [Exceptions: LHRH agonist or antagonist may have been initiated within 30 days prior to enrollment. Bicalutamide may have been given within 60 days of enrollment as long as it has been stopped at least 7 days before enrollment and total duration was no longer than 30 days. This is to allow enrollment of those who have been given bicalutamide as a bridge for LHRH agonist/antagonist. It is highly unlikely a short non-overlapping course of bicalutamide will interact with abiraterone acetate in a measurable way. Previous alpha-reductase inhibitor use allowed IF patient has not been taking for at least 30 days prior to abiraterone acetate initiation, OR if alpha reductase inhibitor was not used as a primary treatment of prostate cancer and the PSA on alpha-reductase inhibitor remains within eligibility when doubled. ] Known serum testosterone ≤ 150 ng/dl or symptoms of hypogonadism (fatigue, hot flashes, hair loss, loss of muscle mass, osteoporosis, low libido, depression) prior to ADT initiation not explained by other medical co-morbidity OR history of testosterone supplement. If questionable, serum testosterone level greater than 150 ng/dl can be used to exclude hypogonadism. Previous malignancy within 3 years other than non-melanomatous skin cancer and non-muscle invasive bladder cancer Previous pelvic radiotherapy that would prevent prostate/SV irradiation Uncontrolled hypertension (systolic BP ≥ 160 mmHg or diastolic BP ≥ 95 mmHg). Patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive therapy History of gastrointestinal disorders that may interfere with the absorption of study drug (including gastric bypass surgery) Concurrent spironolactone use Significant concurrent medical condition that would make prednisone/prednisolone use contraindicated or would interfere with the patient's ability to participate in the trial Receiving any investigational agents currently or within 30 days prior to study screening Prior demonstrated hypersensitivity, intolerance or allergy to abiraterone acetate, prednisone or their excipients Active co-morbidity, defined as follows: Chronic liver disease with cirrhosis (Child-Pugh B or C) or active hepatitis B or C History of pituitary or adrenal dysfunction Poorly controlled diabetes mellitus (A1c >9% or history of complications including peripheral neuropathy, end organ damage, hospitalization, amputation) Poorly controlled glaucoma Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) Class III-IV heart disease or known cardiac ejection fraction measurement of < 50% at baseline. Clinical evidence of active infection of any type, including active or symptomatic viral hepatitis. Known immune deficiency and/or HIV-positive patients Any medical condition that warrants long-term corticosteroid use in excess of study dose Patients taking strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) Any condition that in the opinion of the Principal Investigator, would compromise the well-being of the subject or the study or prevent the subject from meeting or performing the study requirements

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Abiraterone acetate<br>Abiraterone Acetate, Radiotherapy and Short Term Androgen Deprivation. Prednisone will be prescribed concurrently with Abiraterone acetate. | Drug: Abiraterone acetate<br>* 1000 mg orally once a day for 6 months.<br>* Other names: Zytiga;Drug: Androgen deprivation<br>* LHRH analog (at discretion of treating physician) will be administered over 6 months (for example, leuprolide acetate 22.5mg IM or goserelin acetate 10.8mg SC given every 3 months for 2 doses).<br>Radiation: Radiation Therapy<br>* Daily (Monday-Friday) for 8 weeks, final dose of 75-80 Gy<br>Drug: Prednisone<br>* 5 mg tablet once daily for 6 months.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Undetectable PSA (Prostate-Specific Antigen) at 1 Year | The percentage of patients with undetectable PSA after 1 year will be calculated. Undetectable PSA is defined as a measurement of <0.1 ng/mL. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to PSA Nadir | The median time in months to the lowest PSA value from the start of study therapy. | 1 year | 
| PSA Nadir Value | The lowest PSA value from the start of study therapy. | 1 year, 2 years | 
| Percentage of Participants With Biochemical Progression-free Survival (BPFS) | Disease progression defined as Phoenix RTOG definition of nadir PSA + 2ng/ml or initiation of salvage therapy not imaging. The two outcomes use different measures (biochemical as measured by PSA increase vs radiographic as measured by imaging), yielding different results in this case. | 36 and 48 months | 
| Metastasis or Systemic Therapy | Time to either imaging indicating metastasis or beginning a new systemic therapy. This is a distinctly different measure from number 4 above. The two outcomes use different measures (biochemical as measured by PSA increase vs radiographic as measured by imaging), yielding different results in this case. | up to 5 years (60 months) | 
| Testosterone Recovery | Time to testosterone recovery | up to 5 years | 
| PSA < 1.5ng/ml in Setting of Non-castrate Testosterone | Percentage of men with 1, 2, 3, 4 and 5 year PSA < 1.5ng/ml in setting of non-castrate testosterone. | 1 year, 2 years, 3 years, 4 years, 5 years | 
| Safety and Tolerability | The number of patients experiencing an adverse event of at least grade 3 that is possibly, probably, or definitely related to study therapy per CTCAE version 4.0. | 6 months |