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.

Time frame: Baseline, at 12 months

Population: 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 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.

Time frame: 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)

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

Time frame: Baseline, Cycle 12 Day 35

Population: 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 cholesterol, HDL cholesterol, LDL cholesterol and triglycerides were analyzed and reported using a mixed-model for repeated measures.

Time frame: Baseline, Day 35 (Cycle 3, 6, 9 and 12)

Population: 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.

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).

Time frame: Baseline, at 3, 12 and 24 months

Population: 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 estradiol levels was reported.

Time frame: Baseline, Day 35 (Cycle 6 and Cycle 12)

Population: 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.

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.

Time frame: Baseline, at 3, 12 and 24 months

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

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.

Time frame: Baseline, at 3 and 24 months

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

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

Time frame: Baseline, Day 35 (Cycle 3, 6, 9 and 12)

Population: 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.

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

Time frame: Baseline, Day 35 (Cycle 3, 6, 9 and 12)

Population: 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 serum DHT levels was reported.

Time frame: Baseline, Day 35 (Cycle 6 and Cycle 12)

Population: 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.

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 frame: Baseline, at 3, 12, 24 months

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

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.

Time frame: Month 13 to Month 24

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. This outcome measure was planned to be analyzed and reported for LHRHa-based treatment arms.

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

Time frame: From 7 to 24 months

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 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 \[MRI\]).

Time frame: Up to 24 months

Population: 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.

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.

Time frame: From date of 1st dose of study drug to date of last dose of study drug plus 30 days (up to 6 years)

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

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.

Time frame: Up to 24 months

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