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

Phase 2

Completed

Conditions: Prostate Cancer

Interventions: Drug: ARN-509
Drug: LHRH Agonist

Registration Number: NCT01790126

Lead Sponsor: Aragon Pharmaceuticals, Inc.

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 90

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
ARN-509	ARN-509	ARN-509 Tablets, 240 mg/day administered orally
LHRH agonist + ARN-509	ARN-509	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
LHRH agonist + ARN-509	LHRH Agonist	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
LHRH agonist	LHRH Agonist	Choice of LHRHa per investigator discretion/site practice guidelines (e.g., Eligard®, Zoladex®, Lupron Depot®, Trelstar®).

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Functional Assessment of Cancer Therapy - Prostate (FACT-P) Total Score at 12 Months	Baseline, 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.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in FACT-P Total Score at 3 and 24 Months	Baseline, 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.
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	Baseline, 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.
Change From Baseline in EORTC Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Score at 3, 12 and 24 Months	Baseline, 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).
Change From Baseline in Sexual Health Inventory for Men (SHIM) Total Score at 3, 12, 24 Months	Baseline, 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.
Time to Prostate Specific Antigen (PSA) Progression Based on Modified Prostate Cancer Clinical Trials Working Group (PCWG2) Criteria	Up to 24 months	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.
Percentage of Participants Without PSA or Radiographic Progression and With Recovery of Serum Testosterone	Up to 24 months	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 \[MRI\]).
Percentage of Participants With a Serum PSA Less Than 0.2 ng/mL	From 7 to 24 months	Percentage of participants with PSA less than (\<) 0.2 ng/mL after 7 months of protocol therapy were reported.
Change From Baseline in Body Mass Index (BMI)	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 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.
Change From Baseline in Fasting Plasma Glucose	Baseline, Day 35 (Cycle 3, 6, 9 and 12)	The change from baseline in fasting plasma glucose levels was analyzed and reported using a mixed-model for repeated measures.
Change From Baseline in Glycated Hemoglobin (HbA1C)	Baseline, Day 35 (Cycle 3, 6, 9 and 12)	The change from baseline in HbA1C was analyzed and reported using a mixed-model for repeated measures.
Change From Baseline in Cholesterol, High-density Lipoprotein (HDL) Cholesterol, Low-density Lipoprotein (LDL) Cholesterol and Triglycerides	Baseline, Day 35 (Cycle 3, 6, 9 and 12)	Change from baseline in cholesterol, HDL cholesterol, LDL cholesterol and triglycerides were analyzed and reported using a mixed-model for repeated measures.
Change From Baseline in Bone Mineral Density (BMD)	Baseline, Cycle 12 Day 35	Change from baseline in BMD was assessed for femoral neck and lumber spine with DEXA scans.
Median Time to Serum Testosterone Recovery to Greater Than (>) 50 ng/dL (Non-castrate) and > 150 ng/dL	Month 13 to Month 24	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.
Change From Baseline in Serum Dihydrotestosterone (DHT) Levels	Baseline, Day 35 (Cycle 6 and Cycle 12)	Change from baseline in serum DHT levels was reported.
Change From Baseline in Estradiol Levels	Baseline, Day 35 (Cycle 6 and Cycle 12)	Change from baseline in estradiol levels was reported.
Percentage of Participants With Treatment Emergent Adverse Events (TEAEs)	From date of 1st dose of study drug to date of last dose of study drug plus 30 days (up to 6 years)	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.