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Contraceptive Agents, Hormonal

ARN-509 Tablets, 240 mg/day administered orally

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

Choice of LHRHa per investigator discretion/site practice guidelines (e.g., Eligard®, Zoladex®, Lupron Depot®, Trelstar®).

ARN-509

LHRH Agonist

Aragon Pharmaceuticals, Inc Clinical Trial

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.

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

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.

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.

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).

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.

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 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 PSA less than (\<) 0.2 ng/mL after 7 months of protocol therapy were reported.

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.

The change from baseline in fasting plasma glucose levels was analyzed and reported using a mixed-model for repeated measures.

The change from baseline in HbA1C was analyzed and reported using a mixed-model for repeated measures.

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 BMD was assessed for femoral neck and lumber spine with DEXA scans.

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 DHT levels was reported.

Change from baseline in estradiol levels was reported.

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.

Aragon Pharmaceuticals, Inc.

The safety population included all participants who received at least 1 dose of study drug as actually treated.

Participants received LHRHa injections either subcutaneously or intramuscularly as per investigator discretion/site practice guidelines up to 12 months, or shorter duration if evidence of prostate-specific antigen (PSA)/radiographic progression or unacceptable toxicity during protocol therapy or participant/physician withdrawal from the study.

Luteinizing Hormone Releasing Hormone Agonist (LHRHa)

Participants received apalutamide, 240 milligram (mg) soft-gel capsules (8\*30 mg capsules) per day orally up to 12 months, or shorter duration if evidence of PSA/radiographic progression or unacceptable toxicity during protocol therapy or participant/physician withdrawal from the study. With Amendment 7, participants who were receiving the apalutamide soft-gel capsules were switched to the apalutamide tablet formulation (4\*60 mg tablets).

Apalutamide

Participants received LHRHa injections either subcutaneously or intramuscularly as per investigator discretion/site practice guidelines and apalutamide 240 mg soft-gel capsules per day orally up to 12 months, or shorter duration if evidence of PSA/radiographic progression or unacceptable toxicity during protocol therapy or participant/physician withdrawal from the study. With Amendment 7, participants who were receiving the apalutamide soft-gel capsules were switched to the apalutamide tablet formulation (4\*60 mg tablets).

LHRHa + Apalutamide

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

UNITED STATES

Region of Enrollment

EXECUTIVE MEDICAL DIRECTOR

The intent-to-treat (ITT) population included all randomized participants and was classified according to their assigned treatment group, regardless of the actual treatment received.

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

Change at 3 months

Change at 24 months

The ITT population included all randomized participants and was classified according to their assigned treatment group, regardless of the actual treatment received.

Change From Baseline in FACT-P Total Score at 3 and 24 Months

Appetite loss: Change at 3 months

Appetite loss: Change at 12 months

Appetite loss: Change at 24 months

Cognitive functioning: Change at 3 months

Cognitive functioning: Change at 12 months

Cognitive functioning: Change at 24 months

Constipation: Change at 3 months

Constipation: Change at 12 months

Constipation: Change at 24 months

Diarrhoea: Change at 3 months

Diarrhoea: Change at 12 months

Diarrhoea: Change at 24 months

Dyspnoea: Change at 3 months

Dyspnoea: Change at 12 months

Dyspnoea: Change at 24 months

Emotional functioning: Change at 3 months

Emotional functioning: Change at 12 months

Emotional functioning: Change at 24 months

Fatigue: Change at 3 months

Fatigue: Change at 12 months

Fatigue: Change at 24 months

Financial difficulties: Change at 3 months

Financial difficulties: Change at 12 months

Financial difficulties: Change at 24 months

Global health status: Change at 3 months

Global health status: Change at 12 months

Global health status: Change at 24 months

Insomnia: Change at 3 months

Insomnia: Change at 12 months

Insomnia: Change at 24 months

Nausea and vomiting: Change at 3 months

Nausea and vomiting: Change at 12 months

Nausea and vomiting: Change at 24 months

Pain: Change at 3 months

Pain: Change at 12 months

Pain: Change at 24 months

Physical functioning: Change at 3 months

Physical functioning: Change at 12 months

Physical functioning: Change at 24 months

Role functioning: Change at 3 months

Role functioning: Change at 12 months

Role functioning: Change at 24 months

Social functioning: Change at 3 months

Social functioning: Change at 12 months

Social functioning: Change at 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

Incontinence aid: Change at 3 months

Incontinence aid: Change at 12 months

Incontinence aid: Change at 24 months

Bowel symptoms: Change at 3 months

Bowel symptoms: Change at 12 months

Bowel symptoms: Change at 24 months

HTRS: Change at 3 months

HTRS: Change at 12 months

HTRS: Change at 24 months

Sexual activity: Change at 3 months

Sexual activity: Change at 12 months

Sexual activity: Change at 24 months

Sexual functioning: Change at 3 months

Sexual functioning: Change at 12 months

Sexual functioning: Change at 24 months

Urinary symptoms: Change at 3 months

Urinary symptoms: Change at 12 months

Urinary symptoms: Change at 24 months

Change From Baseline in EORTC Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Score at 3, 12 and 24 Months

Change at 12 months

Change From Baseline in Sexual Health Inventory for Men (SHIM) Total Score at 3, 12, 24 Months

Time to Prostate Specific Antigen (PSA) Progression Based on Modified Prostate Cancer Clinical Trials Working Group (PCWG2) Criteria

Modified Intent-to-treat Population (mITT) included subset of ITT population for outcomes related to testosterone recovery, participants who withdrew from the study prior to 24 months after Day 1 were excluded from the analysis. Here, 'N' (number of participants analyzed) signifies number of participants evaluable for this outcome measure.

Percentage of Participants Without PSA or Radiographic Progression and With Recovery of Serum Testosterone

mITT included subset of ITT population for outcomes related to testosterone recovery, participants who withdrew from the study prior to 24 months after Day 1 were excluded from the analysis. Here, 'N' (number of participants analyzed) signifies number of participants evaluable for this outcome measure.

Percentage of Participants With a Serum PSA Less Than 0.2 ng/mL

Change at Cycle 1 Day 1

Change at Cycle 1 Day 28

Change at Cycle 2 Day 28

Change at Cycle 3 Day 35

Change at Cycle 4 Day 28

Change at Cycle 5 Day 28

Change at Cycle 6 Day 35

Change at Cycle 7 Day 28

Change at Cycle 8 Day 28

Change at Cycle 9 Day 35

Change at Cycle 10 Day 28

Change at Cycle 11 Day 28

Change at Cycle 12 Day 35

Endpoint

The safety population included all participants who received at least 1 dose of study drug as actually treated. Here, 'n' (number of participants analyzed) signifies the number of participants analyzed at a specified time point. "Number Analyzed=0" signifies that no participants were evaluated for the specified parameter at that time point.

Change From Baseline in Body Mass Index (BMI)

The ITT population included all randomized participants and was classified according to their assigned treatment group, regardless of the actual treatment received. Here, 'N' (number of participants analyzed) signifies number of participants evaluable for this outcome measure.

Change From Baseline in Fasting Plasma Glucose

Change From Baseline in Glycated Hemoglobin (HbA1C)

Cholesterol: Change at Cycle 3 Day 35

Cholesterol: Change at Cycle 6 Day 35

Cholesterol: Change at Cycle 9 Day 35

Cholesterol: Change at Cycle 12 Day 35

LDL Cholesterol: Change at Cycle 3 Day 35

LDL Cholesterol: Change at Cycle 6 Day 35

LDL Cholesterol: Change at Cycle 9 Day 35

LDL Cholesterol: Change at Cycle 12 Day 35

HDL Cholesterol: Change at Cycle 3 Day 35

HDL Cholesterol: Change at Cycle 6 Day 35

HDL Cholesterol: Change at Cycle 9 Day 35

HDL Cholesterol: Change at Cycle 12 Day 35

Triglycerides: Change at Cycle 3 Day 35

Triglycerides: Change at Cycle 6 Day 35

Triglycerides: Change at Cycle 9 Day 35

Triglycerides: Change at Cycle 12 Day 35

Change From Baseline in Cholesterol, High-density Lipoprotein (HDL) Cholesterol, Low-density Lipoprotein (LDL) Cholesterol and Triglycerides

Femoral Neck

Lumbar Spine

Change From Baseline in Bone Mineral Density (BMD)

> 50 ng/dL

> 150 ng/dL

mITT included subset of ITT population for outcomes related to testosterone recovery, participants who withdrew from the study prior to 24 months after Day 1 were excluded from the analysis. This outcome measure was planned to be analyzed and reported for LHRHa-based treatment arms.

Median Time to Serum Testosterone Recovery to Greater Than (>) 50 ng/dL (Non-castrate) and > 150 ng/dL

Change From Baseline in Serum Dihydrotestosterone (DHT) Levels

Change From Baseline in Estradiol Levels

Percentage of Participants With Treatment Emergent Adverse Events (TEAEs)

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
The Role of Highly Selective Androgen Receptor (AR) Targeted Therapy in Men With Biochemically Relapsed Hormone Sensitive Prostate Cancer	NCT01790126	Prostate Cancer	ARN-509 LHRH Agonist	18 Years -	Aragon Pharmaceuticals, Inc.
The Role of Highly Selective Androgen Receptor (AR) Targeted Therapy in Men With Biochemically Relapsed Hormone Sensitive Prostate Cancer	NCT01790126	Prostate Cancer	ARN-509 LHRH Agonist	18 Years -	Aragon Pharmaceuticals, Inc.

Spots Global Cancer Trial Database for men with biochemically relapsed hormone sensitive prostate cancer