A Study of an Intermittent ADT Approach With Apalutamide Monotherapy in Participants With mCSPC

Study Overview
=================
Brief Summary
-----------------
The purpose of the study is to determine if the intermittent use of androgen-deprivation therapy (ADT) in participants with metastatic castrate-sensitive prostate cancer (mCSPC) who reached a prostate-specific antigen (PSA) level < 0.2 nanograms/millilitres (ng/mL) after 6 months of treatment with apalutamide and ADT combination therapy provides non-inferior radiographic progression-free survival (rPFS) and a reduced burden of hot flashes measured as 18-month percent change in severity adjusted hot flash score.

Official Title
-----------------
A Phase 3, Open-label, Randomized, Prospective Study of Apalutamide With Continued Versus Intermittent Androgen-Deprivation Therapy (ADT) Following PSA Response in Participants With Metastatic Castration-Sensitive Prostate Cancer (mCSPC)

Conditions
-----------------
Metastatic Castrate-sensitive Prostate Cancer

Intervention / Treatment
-----------------
* Drug: Apalutamide
* Drug: Androgen-deprivation Therapy (ADT)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of prostate cancer prior to screening with histologically or cytologically confirmed adenocarcinoma of the prostate Metastatic prostate cancer disease documented by conventional imaging (example, computed tomography [CT], magnetic resonance imaging [MRI], or bone scan) and/or next-generation imaging [NGI] demonstrating greater than equal (>=) 2 distinct extraprostatic sites of metastasis Have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1. Participants with ECOG PS 2 or 3 are eligible for the study if the ECOG PS score is related to stable physical limitations (example, wheelchair-bound due to prior spinal cord injury) and not related to prostate cancer or associated therapy A participant must agree not to plan to conceive a child while enrolled in this study or within 3 months after the last dose of study treatment Must be able to take whole apalutamide tablets by swallowing alone or with another vehicle (example, applesauce) Assigned male at birth, inclusive of all gender identities Participants who have undergone a bilateral orchidectomy and/or who are actively taking gender-affirming hormone therapy as part of their gender affirming care Exclusion Criteria: History of seizure or known condition that has been determined to significantly predispose to seizure per investigator Pelvic lymph nodes as only site of metastasis Known allergies, hypersensitivity, or intolerance to excipients of apalutamide Any of the following within 6 months prior to screening: severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, uncontrolled hypertension, clinically significant arterial or venous thromboembolic events Gastrointestinal disorder affecting absorption

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (Intermittent ADT Group)<br>Participants with PSA level <0.2 ng/mL after 6 months of treatment with Apalutamide and ADT during initial treatment phase, will enter main treatment phase and treated with apalutamide with intermittent ADT per protocol or followed up for at least 18 months from Day 1 of Cycle 7 (each cycle 28 days) or have discontinued the study, whichever occurs first. | Drug: Apalutamide<br>* Apalutamide will be administered orally from Day 1 of Cycle 1 till 6 months in initial treatment phase and then in main treatment phase from Day 1 of Cycle 7 up to at least 18 months.<br>Drug: Androgen-deprivation Therapy (ADT)<br>* The choice of ADT will be at discretion of the Investigator. Dosing (dose and frequency of administration) will be consistent with the prescribing information.<br>|
| Experimental: Arm B (Continuous ADT Group)<br>Participants with PSA level <0.2 ng/mL after 6 months of treatment with Apalutamide and ADT during initial treatment phase, will enter main treatment phase and continue to receive apalutamide plus ADT or followed up for at least 18 months from Day 1 of Cycle 7 (each cycle 28 days) or have discontinued the study, whichever occurs first. | Drug: Apalutamide<br>* Apalutamide will be administered orally from Day 1 of Cycle 1 till 6 months in initial treatment phase and then in main treatment phase from Day 1 of Cycle 7 up to at least 18 months.<br>Drug: Androgen-deprivation Therapy (ADT)<br>* The choice of ADT will be at discretion of the Investigator. Dosing (dose and frequency of administration) will be consistent with the prescribing information.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With 18-Months Radiographic Progression-free Survival (rPFS) | rPFS is defined as the duration from the date of randomization to the date of first documentation of confirmed radiographic progressive disease or death due to any cause, whichever occurs first. rPFS will be assessed by investigators using conventional imaging (computed tomography [CT]/magnetic resonance imaging [MRI] and 99mTc bone scans). | From randomization (Day 1 of Cycle 7) up to 18 months | 
| Percent Change From Randomization in Severity of Adjusted Hot Flash Score at 18 Months | Severity adjusted hot flash score will be calculated from the hot flash diary which will be daily filled by the participants. | From randomization (Day 1 of Cycle 7) up to 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Percentage Changes From Randomization in Severity Adjusted Hot Flash Score and Hot Flash Frequency | Severity adjusted hot flash score and hot flash frequency will be calculated from the hot flash diary which will be daily filled by the participants. | From randomization (Day 1 of Cycle 7), up to 3 years 3 months | 
| Second Progression-free Survival (PFS2) | PFS2 is defined as the duration from the date of randomization to the first occurrence of investigator-determined disease progression on the first subsequent therapy after study drug discontinuation or death, whichever occurs first. | From randomization (Day 1 of Cycle 7) up to 3 years 3 months | 
| Overall Survival (OS) | Overall survival time is defined as the duration from the date of randomization to the date of death from any cause. | From randomization (Day 1 of Cycle 7) up to 3 years 3 months | 
| Prostate Cancer-specific Survival | Prostate cancer-specific survival is defined as the duration from the date of randomization to the date of death from any cause. | From randomization (Day 1 Cycle 7) up to 3 years 3 months | 
| Serum Prostate Specific Antigen (PSA) Evaluations | Serum PSA evaluations will be measured according to Prostate Cancer Working Group 3 (PCWG3) criteria. | From randomization (Day 1 of Cycle 7) up to 3 years 3 months | 
| Duration of Time on Androgen-deprivation Therapy (ADT) | Duration of time on ADT will be reported for all participants. | From randomization (Day 1 of Cycle 7) up to 3 years 3 months | 
| Time to First ADT Restart | Time to first ADT restart will be reported. | From randomization (Day 1 of Cycle 7) up to 3 years 3 months | 
| Duration of Time with Testosterone Level Less than (<) 50 nanograms per millilitre (ng/mL) | Duration of time with testosterone level <50 ng/mL will be reported. | From randomization (Day 1 of Cycle 7) up to 3 years 3 months | 
| Time to Recovery of Testosterone >50 nanogram per decilitre (ng/dL) | The testosterone recovery, defined as a serum testosterone >50 ng/dL will be analyzed. | From randomization (Day 1 of Cycle 7) up to 3 years 3 months | 
| Time to Recovery of Testosterone Greater Than or Equal (>=) Screening Testosterone Level | Time to recovery of testosterone >= screening testosterone level will be reported. | From randomization (Day 1 of Cycle 7) up to 3 years 3 months | 
| Time to Testosterone Recovery to Normal Range (>270 ng/dL) | Time to serum testosterone recovery to normal range (>270 ng/dL) will be reported. | From randomization (Day 1 of Cycle 7) up to 3 years 3 months | 
| Time to Metastatic Castration-resistant Prostate Cancer (mCRPC) | Time to mCRPC will be reported. | From randomization (Day 1 of Cycle 7) up to 3 years 3 months | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/ biological agent under study. An SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, leads to a congenital anomaly/birth defect in the offspring of a participant, or is an important medical event. | Initial Treatment Phase: From Day 1 of Cycle 1 (each cycle 28 days) up to end of Cycle 6 (6 month); Main Treatment Phase: Day 1 of Cycle 7 up to end of study (up to 3 years 9 months) | 
| Number of Participants with Abnormal Clinical Laboratory Parameters | Number of participants with abnormal clinical laboratory parameters (hematology, clinical chemistry) will be reported. | From Cycle 1 Day 1 up to 3 years 9 months | 
| Number of Participants with Abnormal Vital Sign Parameters | Number of participants with abnormal vital sign parameters (temperature, pulse/heart rate, respiratory rate, and blood pressure) will be reported. | From Cycle 1 Day 1 up to 3 years 9 months | 
| Number of Participants with Abnormal Physical Examination Parameters | Number of Participants with Abnormal physical examination parameters will be reported. | From Cycle 1 Day 1 up to 3 years 9 months | 
| Hot Flash Related Daily Interference Score (HFRDIS) | The HFRDIS is a 10-item scale assessing how much hot flashes interfered with various aspects of a participant's daily life. All items are rated on a 0-10 numerical rating scale with 0 anchored as Do Not Interfere and 10 as Completely Interfere. A total score is computed by summing items. Higher scores indicate higher interference due to hot flashes and thus, greater impact on quality of life. | Up to 3 years 9 months | 
| Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Score | The EORTC-QLQ-C30 (Version 3), is a self-administered, 30-item questionnaire measuring the HRQoL of participants with cancer. The recall period for most items is the past week. EORTC-QLQ-C30 includes 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), a global health status/quality of life scale, and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The item and scale scores are transformed to a 0 to 100 scale. A high scale score represents a higher response level. Thus, a high score for a functional scale represents a high/healthy level of functioning and a high score for the global health status represents high HRQoL, but a high score for a symptom scale/item represents a high level of symptomatology/problems. | Baseline up to 3 years 9 months | 
| Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire -Prostate Cancer Module (EORTC-PR25) Questionnaire | The EORTC-PR25 questionnaire is a supplement to the EORTC-QLQ-C30 questionnaire and is designed to assess symptoms related to prostate cancer, its treatment, and aspects of life related to this type of cancer. | Baseline up to 3 years 9 months | 
| Change From Baseline in European Organization for the Research and Treatment of Cancer (EORTC) Customized Study Form | EORTC customized study form will include 3 questions that are not included on the QLQ-30 or PR25 forms. The items assess rash, side effect burden, and dry mouth. | Baseline up to 3 years 9 months | 
| Change From Baseline in Patient-Reported Outcomes Measurement Information System Cognitive Function (PROMIS-Cog) Questionnaire | The PROMIS-Cog is a self-administered fixed-length questionnaire of 8 items from the PROMIS item bank relating to cognitive function. The raw domain scores are converted to standardized T-scores with a mean of 50 and a standard deviation of 10. Higher scores indicate better cognitive functioning. | Baseline up to 3 years 9 months | 
| Change From Baseline in Memorial Anxiety Scale for Prostate Cancer (MAX-PC) Questionnaire | The MAX-PC is a patient-reported questionnaire measuring prostate cancer specific anxiety. It consists of 18 items in 3 domains: It includes 11 items regarding prostate cancer anxiety, scored 0-33; 3 items regarding prostate-specific Antigen Anxiety, scored 0-9; and 4 items regarding fear of recurrence, scored 0-12. Total score ranges from 0-54 with higher scores indicating greater anxiety. | Baseline up to 3 years 9 months | 
| Change From Baseline in Patient Health Questionnaire (PHQ-9) Questionnaire | The PHQ-9 is self-administered, 9-item questionnaire measuring symptoms of depression. The recall period for all items is the past 2 weeks. The items include diminished interest or pleasure, depressed mood, insomnia/hypersomnia, fatigue or loss of energy, weight loss or weight gain/appetite loss or appetite gain, feelings of worthlessness, diminished concentration/indecisiveness, psychomotor agitation/retardation, and thoughts of death/suicide. Higher scores indicate more severe depressive symptoms. | Baseline up to 3 years 9 months | 
| Change From Baseline in Patient Global Impression of Severity scale (PGIS) Questionnaire | The PGIS is a self-administered, single item questionnaire measuring patients' impression of disease severity. Participants will be asked to rate their disease severity over the past 7 days using the following 5-point scale: 1 = None, 2 = Mild, 3 = Moderate, 4 = Severe, and 5 = Very severe. Higher scores indicate greater severity of fatigue. | Baseline up to 3 years 9 months | 
| Change From Baseline in Patient Global Impression of Change (PGIC) Questionnaire | The PGIC is self-administered, single-item questionnaire measuring patients' impression of change in disease symptoms. Participants will be asked to rate their current symptoms as compared to when they started the study, using the following 7-point scale: 1 = Much better, 2 = Moderately better, 3 = A little better, 4 = No change, 5 = A little worse, 6 = Moderately worse, and 7 = Much worse. A higher PGIC score indicates greater worsening of symptoms. | Baseline up to 3 years 9 months | 
| Time to Recovery From Baseline as Assessed by EORTC-QLQ-C30 | Time to recovery from baseline as assessed by EORTC-QLQ-C30 will be reported. The EORTC-QLQ-C30 (Version 3), is a self-administered, 30-item questionnaire measuring the HRQoL of participants with cancer. The recall period for most items is the past week. EORTC-QLQ-C30 includes 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), a global health status/quality of life scale, and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The item and scale scores are transformed to a 0 to 100 scale. A high scale score represents a higher response level. Thus, a high score for a functional scale represents a high/healthy level of functioning and a high score for the global health status represents high HRQoL, but a high score for a symptom scale/item represents a high level of symptomatology/problems. | Baseline up to 3 years 9 months | 
| Time to Recovery From Baseline as Assessed by EORTC-PR25 | Time to recovery from baseline as assessed by EORTC-PR25 will be reported. The EORTC-PR25 questionnaire is a supplement to the EORTC-QLQ-C30 questionnaire and is designed to assess symptoms related to prostate cancer, its treatment, and aspects of life related to this type of cancer. | Baseline up to 3 years 9 months | 
| Time to Recovery From Baseline as Assessed by EORTC Customized Study Form | Time to recovery from baseline as assessed by EORTC customized study form will be reported. EORTC customized study form will include 3 questions that are not included on the QLQ-30 or PR25 forms. The items assess rash, side effect burden, and dry mouth. | Baseline up to 3 years 9 months | 
| Time to Recovery From Baseline as Assessed by MAX-PC | Time to recovery from baseline as assessed by MAX-PC will be reported. The MAX-PC is a patient-reported questionnaire measuring prostate cancer specific anxiety. It consists of 18 items in 3 domains: It includes 11 items regarding prostate cancer anxiety, scored 0-33; 3 items regarding prostate-specific Antigen Anxiety, scored 0-9; and 4 items regarding fear of recurrence, scored 0-12. Total score ranges from 0-54 with higher scores indicating greater anxiety. | Baseline up to 3 years 9 months | 
| Time to Recovery From Baseline as Assessed by PHQ-9 | Time to recovery from baseline as assessed by PHQ-9 will be reported. The PHQ-9 is self-administered, 9-item questionnaire measuring symptoms of depression. The recall period for all items is the past 2 weeks. The items include diminished interest or pleasure, depressed mood, insomnia/hypersomnia, fatigue or loss of energy, weight loss or weight gain/appetite loss or appetite gain, feelings of worthlessness, diminished concentration/indecisiveness, psychomotor agitation/retardation, and thoughts of death/suicide. Higher scores indicate more severe depressive symptoms. | Baseline up to 3 years 9 months | 
| Time to Recovery From Baseline as Assessed by PGIS | Time to recovery from baseline as assessed by PGIS will be reported. The PGIS is a self-administered, single item questionnaire measuring patients' impression of disease severity. Participants will be asked to rate their disease severity over the past 7 days using the following 5-point scale: 1 = None, 2 = Mild, 3 = Moderate, 4 = Severe, and 5 = Very severe. Higher scores indicate greater severity of fatigue. | Baseline up to 3 years 9 months | 
| Time to Recovery From Baseline as Assessed by PGIC | Time to recovery from baseline as assessed by PGIC will be reported. The PGIC is self-administered, single-item questionnaire measuring patients' impression of change in disease symptoms. Participants will be asked to rate their current symptoms as compared to when they started the study, using the following 7-point scale: 1 = Much better, 2 = Moderately better, 3 = A little better, 4 = No change, 5 = A little worse, 6 = Moderately worse, and 7 = Much worse. A higher PGIC score indicates greater worsening of symptoms. | Baseline up to 3 years and 9 months | 
| Time to Recovery From Baseline as Assessed by PROMIS-Cog | Time to recovery from baseline as assessed by PROMIS-Cog will be reported. The PROMIS-Cog is a self-administered fixed-length questionnaire of 8 items from the PROMIS item bank relating to cognitive function. The raw domain scores are converted to standardized T-scores with a mean of 50 and a standard deviation of 10. Higher scores indicate better cognitive functioning. | Baseline up to 3 years 9 months | 
| Time to Deterioration in EORTC-QLQ-C30 Over Time | Time to deterioration in EORTC-QLQ-C30 over time will be reported. The EORTC-QLQ-C30 (Version 3), is a self-administered, 30-item questionnaire measuring the HRQoL of participants with cancer. The recall period for most items is the past week. EORTC-QLQ-C30 includes 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), a global health status/quality of life scale, and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The item and scale scores are transformed to a 0 to 100 scale. A high scale score represents a higher response level. Thus, a high score for a functional scale represents a high/healthy level of functioning and a high score for the global health status represents high HRQoL, but a high score for a symptom scale/item represents a high level of symptomatology/problems. | Up to 3 years 9 months | 
| Time to Deterioration in EORTC-PR25 Over Time | Time to deterioration in EORTC-PR25 over time will be reported. The EORTC-PR25 questionnaire is a supplement to the EORTC-QLQ-C30 questionnaire and is designed to assess symptoms related to prostate cancer, its treatment, and aspects of life related to this type of cancer. | Up to 3 years 9 months | 
| Time to Deterioration in EORTC Customized Study Form Over Time | Time to deterioration in EORTC Customized Study Form over time will be reported. EORTC customized study form will include 3 questions that are not included on the QLQ-30 or PR25 forms. The items assess rash, side effect burden, and dry mouth. | Up to 3 years 9 months | 
| Time to Deterioration as per PROMIS-Cog Questionnaire Over Time | Time to deterioration as per PROMIS-Cog questionnaire over time will be reported. The PROMIS-Cog is a self-administered fixed-length questionnaire of 8 items from the PROMIS item bank relating to cognitive function. The raw domain scores are converted to standardized T-scores with a mean of 50 and a standard deviation of 10. Higher scores indicate better cognitive functioning. | Up to 3 years 9 months | 
| Time to Deterioration in MAX-PC Questionnaire Over Time | Time to deterioration in MAX-PC questionnaire over time will be reported. The MAX-PC is a patient-reported questionnaire measuring prostate cancer specific anxiety. It consists of 18 items in 3 domains: It includes 11 items regarding prostate cancer anxiety, scored 0-33; 3 items regarding prostate-specific Antigen Anxiety, scored 0-9; and 4 items regarding fear of recurrence, scored 0-12. Total score ranges from 0-54 with higher scores indicating greater anxiety. | Up to 3 years 9 months | 
| Time to Deterioration as per PHQ-9 Questionnaire Over Time | Time to deterioration as per PHQ-9 questionnaire over time will be reported. The PHQ-9 is self-administered, 9-item questionnaire measuring symptoms of depression. The recall period for all items is the past 2 weeks. The items include diminished interest or pleasure, depressed mood, insomnia/hypersomnia, fatigue or loss of energy, weight loss or weight gain/appetite loss or appetite gain, feelings of worthlessness, diminished concentration/indecisiveness, psychomotor agitation/retardation, and thoughts of death/suicide. Higher scores indicate more severe depressive symptoms. | Up to 3 years 9 months | 
| Time to Deterioration in PGIS Questionnaire Over Time | Time to deterioration as per PGIS questionnaire over time will be reported. The PGIS is a self-administered, single item questionnaire measuring patients' impression of disease severity. Participants will be asked to rate their disease severity over the past 7 days using the following 5-point scale: 1 = None, 2 = Mild, 3 = Moderate, 4 = Severe, and 5 = Very severe. Higher scores indicate greater severity of fatigue. | Up to 3 years 9 months | 
| Time to Deterioration as per PGIC Questionnaire Over Time | Time to Deterioration as per PGIC questionnaire over time will be reported. The PGIC is self-administered, single-item questionnaire measuring patients' impression of change in disease symptoms. Participants will be asked to rate their current symptoms as compared to when they started the study, using the following 7-point scale: 1 = Much better, 2 = Moderately better, 3 = A little better, 4 = No change, 5 = A little worse, 6 = Moderately worse, and 7 = Much worse. A higher PGIC score indicates greater worsening of symptoms. | Up to 3 years 9 months |