Evaluating Hormone Therapy to Achieve Optimal Doses in Metastatic Prostate Cancer

Overall survival, defined as the time from date of randomisation to date of death from any cause, and those who are alive are censored at the date last known to be alive. This will be assessed for non-inferiority using a margin for the absolute risk difference at 2 years of ≤4 percentage points, between reduced and standard dose ARPI arms. A hierarchical approach will be applied to all 3 primary outcome measures, in which each analysis (in turn) should yield a p-value of <0.05 in the following ranked order:

• Non-inferiority for overall survival
• Superiority of a mean difference in QoL fatigue score (expected to be ≥7 units)
• Superiority for the percentage of patients who do not discontinue ARPI due to adverse events

Adverse events will be analysed using CTCAE Version 6.0 categorisation (all grades) for patients who permanently discontinue APRI. A hierarchical approach will be applied to all 3 primary outcome measures, in which each analysis (in turn) should yield a p-value of <0.05 in the following ranked order:

• Non-inferiority for overall survival
• Superiority of a mean difference in QoL fatigue score (expected to be ≥7 units)
• Superiority for the percentage of patients who do not discontinue ARPI due to adverse events

Fatigue assessed using the EORTC 12-point fatigue scale (QLQ-FA12). A hierarchical approach will be applied to all 3 primary outcome measures, in which each analysis (in turn) should yield a p-value of <0.05 in the following ranked order:

• Non-inferiority for overall survival
• Superiority of a mean difference in QoL fatigue score (expected to be ≥7 units)
• Superiority for the percentage of patients who do not discontinue ARPI due to adverse events

Toxicities using the CTCAE Version 6.0 categorisation (all grades). Events that would be of special interest include hypertension, rash, hot flushes, cardiovascular events, and falls.

Failure-free survival (FFS) defined as the time from the date of randomisation to the date of the first of the following forms of treatment failure: biochemical (prostate-specific antigen (PSA)) failure; progression of local, lymph-node, or distant metastases; starting another line of therapy, or death from prostate cancer. Patients without an FFS event would be censored at the date last known to be alive. Stopping treatment for reasons other than the events listed above would not be considered an FFS event.

• Proportion of patients who have rising PSA (PSA progression is defined as ≥25% increase and at least a 2 ng/mL absolute increase above the nadir, confirmed by a second value ≥3 weeks later) at 1 and 2 years post randomisation.
• Proportion of patients who have PSA only progression: PSA rise of ≥25% above lowest PSA result compared to baseline at 1 and 2 years post randomisation.
• Proportion of patients who have significant clinical progression, including new cancer related symptoms, as determined by the local clinical team: at 1 and 2 years post randomisation.
• Proportion of patients who have radiological progression as determined by the local clinical team: at 1 and 2 years post randomisation.
• Proportion of patients who achieve PSA nadir of <0.2 within 12 months of starting therapy (primarily for mHSPC patients).

Adherence: proportion of patients who stop ARPI permanently due to reasons other than disease progression, at 1 and 2 years (reasons will be recorded).

Adherence: the duration of ARPI (in months) from the time of starting therapy.

Proportion of patients who have a dose reduction of ARPI (from their starting dose, in either arm) due to adverse events.

Proportion of patients (dose reduction arm) who have their dose increased (reasons will be recorded).

Quality of Life assessments will be undertaken using EORTC QLQ-C30 questionnaire using Likert score (26 questions scored: 1=not at all, 2=a little, 3=quite a bit, 4=very much; 2 questions scored: 1-7, 1=very poor, 7=excellent). Descriptions of mean change in EORTC QLQ scores will be presented and compared to baseline values from pre-treatment.

Quality of Life assessments will be undertaken using EORTC QLQ-C30 which will include QLQ-IL249 questions using Likert score (22 questions scored: 1=not at all, 2=a little, 3=quite a bit, 4=very much). Descriptions of mean change in EORTC QLQ scores will be presented and compared to baseline values from pre-treatment.

Quality of Life assessments will be undertaken using EQ-5D-5L (self-reported) questionnaire using a combination of Likert score (5 questions with 5 dimensions of abilities) and visual analogue score (scored 0-100, 0=worst, 100=best). Descriptions of mean change in EQ-5D-5L scores will be presented and compared to baseline values from pre-treatment.