The Role of Highly Selective Androgen Receptor (AR) Targeted Therapy in Men With Biochemically Relapsed Hormone Sensitive Prostate Cancer

Study Overview
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Brief Summary
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The proposed clinical trial will study the effects of 12 months of therapy with ARN-509 alone, or in combination with an LHRH agonist (LHRHa), each compared with LHRHa alone, in men with a rapidly rising serum PSA after prior definitive local therapy for prostate cancer. The endpoints selected reflect measurable short term effects of androgen deprivation therapy (ADT), including quality of life and several metabolic parameters. In addition, the relative effect of each treatment strategy on PSA suppression as well as testosterone recovery (and subsequent PSA progression) after 12 months of therapy will be evaluated.

Official Title
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The Role of Highly Selective Androgen Receptor (AR) Targeted Therapy in Men With Biochemically Relapsed Hormone Sensitive Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: ARN-509
* Drug: LHRH Agonist


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Histologically proven adenocarcinoma of the prostate Rising PSA after prior definitive local therapy (radical prostatectomy, external beam radiation, or brachytherapy) or combination of radical prostatectomy and radiotherapy with curative intent PSA doubling time less than or equal to 12 months No evidence of metastatic disease on imaging by whole body bone scan and computerized tomography (CT) or Magnetic Resonance Imaging (MRI) of the abdomen/pelvis within 6 weeks prior to randomization Minimum PSA 1.0 ng/mL if prior radical prostatectomy +/- adjuvant or salvage radiation; nadir + 2.0 ng/mL if prior RT without prior radical prostatectomy Prior androgen deprivation therapy (ADT) allowed if last dose was greater than (>) 6 months prior to randomization No prior androgen deprivation therapy (ADT) or anti-androgen for biochemical relapse Serum testosterone > 150 ng/dL at study entry No history of seizures or medical conditions which may lower seizure threshold Key Exclusion Criteria: Use of 5-alpha reductase antagonist (i.e. finasteride, dutasteride) within 6 weeks prior to randomization Use of antiandrogen (e.g. flutamide, nilutamide, bicalutamide) within 6 weeks prior to randomization Prior bilateral orchiectomy Prior treatment with ADT for biochemically relapsed prostate cancer. Prior ADT as neo-adjuvant, concurrent, and/or adjuvant treatment following salvage radiation therapy or prostatectomy for biochemically relapsed disease is allowed provided last dose of ADT is greater than (>) 6 months prior to randomization and the Screening serum testosterone level is greater than or equal to (≥)150 ng/dL Use of systemic steroids at an equivalent dose of prednisone 5 mg/day or higher at randomization Any history of seizures or medical condition which lowers seizure threshold

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ARN-509<br>ARN-509 Tablets, 240 mg/day administered orally | Drug: ARN-509<br> <br> |
| Active Comparator: LHRH agonist + ARN-509<br>Choice of LHRHa per investigator discretion/site practice guidelines (e.g, Eligard®, Zoladex®, Lupron Depot®, Trelstar®) and ARN-509 Tablets, 240 mg/day administered orally | Drug: ARN-509<br> <br> Drug: LHRH Agonist<br> <br> * Other names: Trelstar®;|
| Active Comparator: LHRH agonist<br>Choice of LHRHa per investigator discretion/site practice guidelines (e.g., Eligard®, Zoladex®, Lupron Depot®, Trelstar®). | Drug: LHRH Agonist<br> <br> * Other names: Trelstar®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Functional Assessment of Cancer Therapy - Prostate (FACT-P) Total Score at 12 Months | FACT-P assesses symptoms/problems related to prostate carcinoma and its treatment. It is a combination of the FACT- General + the Prostate Cancer Subscale (PCS). The FACT-General (FACT-G) is a 27 item Quality of Life (QoL) measure that provides a total score as well as subscale scores: Physical (0-28), Functional (0-28), Social (0-28), and Emotional Well-being (0-24). The total score range is between 1-108, higher scores indicates better for total score and subscale scores. PCS is a 12-item prostate cancer subscale that asks about symptoms and problems specific to prostate cancer (Range 0-48, higher scores better). The FACT-P total score is the sum of all 5 subscale scores of the FACT-P questionnaire and ranges from 0-156. Higher scores indicate higher degree of functioning and better quality of life. | Baseline, at 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in FACT-P Total Score at 3 and 24 Months | FACT-P assesses symptoms/problems related to prostate carcinoma and its treatment. It is a combination of the FACT- General + the Prostate Cancer Subscale (PCS). The FACT-General (FACT-G) is a 27 item Quality of Life (QoL) measure that provides a total score as well as subscale scores: Physical (0-28), Functional (0-28), Social (0-28), and Emotional Well-being (0-24). The total score range is between 1-108, higher scores indicates better for total score and subscale scores. PCS is a 12-item prostate cancer subscale that asks about symptoms and problems specific to prostate cancer (Range 0-48, higher scores better). The FACT-P total score is the sum of all 5 subscale scores of the FACT-P questionnaire and ranges from 0-156. Higher scores indicate higher degree of functioning and better quality of life. | Baseline, at 3 and 24 months | 
| Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Score at 3, 12 and 24 Months | EORTC QLQ-C30 is a 30 items self-reporting questionnaire resulting in 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 Global Health Status (GHS) scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single symptom items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Questionnaire includes 28 items with 4-point Likert type responses from 1-not at all to 4-very much to assess functioning and symptoms; 2 items with 7-point Likert scales (1= poor and 7= excellent) for global health and overall health related quality of life. Scores are transformed to 0 to 100 scale, with higher scores representing better GHS, better functioning, and more symptoms. | Baseline, at 3, 12 and 24 months | 
| Change From Baseline in EORTC Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Score at 3, 12 and 24 Months | EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It Consist of 25 questions distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions on a 4 point scale (1 'Not at all' to 4 'Very much'). All raw domain scores are linearly transformed to a 0-100 scale, with higher scores reflecting either more symptoms (urinary, bowel, hormonal treatment-related symptoms) or higher levels of activity or functioning (sexual). | Baseline, at 3, 12 and 24 months | 
| Change From Baseline in Sexual Health Inventory for Men (SHIM) Total Score at 3, 12, 24 Months | The SHIM is a well validated abridged 5-item of the 15-item International Index of Erectile Function, which has been extensively studied in men with erectile dysfunction due to various etiologies, including prostate cancer-related therapies. It consists of 5 items pertaining to sexual functioning, with scores ranging from 0-5 for most items. The total score is obtained by adding all five item scores, and can range from 5 to 25. Higher scores indicate higher level of sexual function and less erectile dysfunction. | Baseline, at 3, 12, 24 months | 
| Time to Prostate Specific Antigen (PSA) Progression Based on Modified Prostate Cancer Clinical Trials Working Group (PCWG2) Criteria | PSA progression was defined as a rise to greater than 50 percent (%) of the baseline serum PSA or rise of 2 nanogram per milliliter (ng/mL) or more above the nadir, whichever is higher, confirmed by repeat measurement at least 2 weeks later. | Up to 24 months | 
| Percentage of Participants Without PSA or Radiographic Progression and With Recovery of Serum Testosterone | Percentage of participants without evidence of PSA or radiographic progression during the 24-month treatment period and with recovery of serum testosterone at 24 months were reported. Testosterone recovery was defined as a serum testosterone greater than (>) 150 nanogram per deciliter (ng/dL). PSA progression was defined as a rise to greater than 50 percent (%) of the baseline serum PSA or rise of 2 nanogram per milliliter (ng/mL) or more above the nadir, whichever is higher, confirmed by repeat measurement at least 2 weeks later. Radiographic progression was defined as the detection of new metastasis on either bone scan or cross-sectional imaging (computed tomography [CT] or magnetic resonance imaging [MRI]). | Up to 24 months | 
| Percentage of Participants With a Serum PSA Less Than 0.2 ng/mL | Percentage of participants with PSA less than (<) 0.2 ng/mL after 7 months of protocol therapy were reported. | From 7 to 24 months | 
| Change From Baseline in Body Mass Index (BMI) | Change from baseline in BMI was reported. BMI was calculated as 'body weight in kg/(height in meters)* (height in meters)'. Endpoint values are from the last measurement within the analysis period. | Baseline, Day 1 (Cycle 1), Day 28 (Cycle 1, 2, 4, 5, 7, 8, 10 and 11), Day 35 (Cycle 3, 6, 9 and 12) and endpoint (up to 24 months) | 
| Change From Baseline in Fasting Plasma Glucose | The change from baseline in fasting plasma glucose levels was analyzed and reported using a mixed-model for repeated measures. | Baseline, Day 35 (Cycle 3, 6, 9 and 12) | 
| Change From Baseline in Glycated Hemoglobin (HbA1C) | The change from baseline in HbA1C was analyzed and reported using a mixed-model for repeated measures. | Baseline, Day 35 (Cycle 3, 6, 9 and 12) | 
| Change From Baseline in Cholesterol, High-density Lipoprotein (HDL) Cholesterol, Low-density Lipoprotein (LDL) Cholesterol and Triglycerides | Change from baseline in cholesterol, HDL cholesterol, LDL cholesterol and triglycerides were analyzed and reported using a mixed-model for repeated measures. | Baseline, Day 35 (Cycle 3, 6, 9 and 12) | 
| Change From Baseline in Bone Mineral Density (BMD) | Change from baseline in BMD was assessed for femoral neck and lumber spine with DEXA scans. | Baseline, Cycle 12 Day 35 | 
| Median Time to Serum Testosterone Recovery to Greater Than (>) 50 ng/dL (Non-castrate) and > 150 ng/dL | The time to serum testosterone recovery to > 50 ng/dL and > 150 ng/dL from Month 13 to Month 24 of protocol therapy was reported. | Month 13 to Month 24 | 
| Change From Baseline in Serum Dihydrotestosterone (DHT) Levels | Change from baseline in serum DHT levels was reported. | Baseline, Day 35 (Cycle 6 and Cycle 12) | 
| Change From Baseline in Estradiol Levels | Change from baseline in estradiol levels was reported. | Baseline, Day 35 (Cycle 6 and Cycle 12) | 
| Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) | An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal (investigational or non-investigational) product, whether or not related to that medicinal (investigational or non-investigational) product. Treatment-emergent adverse events are those that occurred between the date of 1st dose of study drug and date of last dose of study drug plus 30 days. | From date of 1st dose of study drug to date of last dose of study drug plus 30 days (up to 6 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Men with Biochemically Relapsed Hormone Sensitive Prostate Cancer