Evaluating Hormone Therapy to Achieve Optimal Doses in Metastatic Prostate Cancer

Phase 3RecruitingNCT07751133

University College, London1,500 enrolled

Overview

The goal of this phase 3 clinical trial is to determine the clinical effectiveness and cost effectiveness of using lower doses of Androgen Receptor Pathway Inhibitors (ARPI) to treat patients with prostate cancer that has spread (metastasized). The main questions it aims to answer are: 1. if overall survival for reduced dose ARPI is not worse than standard dose ARPI when treating patients with metastatic prostate cancer, and 2. that fatigue (extreme exhaustion) and not stopping ARPI permanently (due to adverse effects) are better than average with the reduced dose. Participants will: * Be randomised to take full dose (100%) of ARPI or half dose (50%) of ARPI. * Receive standard of care ADT. * Be on treatment for approximately 3 years according to standard of care. * Have clinic assessments and visits in clinic or remotely, as per their treating hospital's standard routine local practice in line with standard of care. Additional visits are not expected. * Complete quality of life questionnaires at week 0 (pre-treatment) and weeks 4, 16, 32, 48 and 64. * Keep a diary of their symptoms. Translational research samples will be collected as follows: * Blood samples at week 0 (pre-treatment) and weeks 24, 32, 48 and at disease progression. * Urine samples at week 0 (pre-treatment) and week 24 and at disease progression. * FFPE Tumour: Routinely collected diagnostic blocks. The duration of follow-up is approximately 3 years after the last patient is recruited (minimum follow-up is 3 years; maximum follow-up is approximately 6 years for the the first patient recruited) and the trial is expected to complete August 2032 (Last Patient Last Visit).

ENHANCE is a clinical trial in patients with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) or castration-resistant prostate cancer (mCRPC) who are clinically suitable for and planned to commence Androgen Receptor Pathway Inhibitors (ARPI) plus standard Androgen Deprivation Therapy (ADT). Participants will be randomised according to the trial's stratification criteria to receive standard recommended (100%) dose or reduced dose (50%) of ARPI (enzalutamide, apalutamide, darolutamide or abiraterone) and take ADT. Participants will have hospital clinic visits according to the trial visits assessment schedule as detailed in the trial protocol and in line with the recruiting centers standard of care policy. Participants will complete questionnaires and keep a symptoms diary in accordance with the assessments schedule. Participants will provide urine, blood and tumour diagnostic biopsy samples for translational research purposes according to the assessments schedule which will be sent to and processed by a Central Laboratory located in Manchester.

Eligibility

Sex: MALEMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Adult males (male sex at birth) aged 18 years or older 2. Newly histologically or cytologically diagnosed prostate cancer (adenocarcinoma) that is metastatic hormone-sensitive (mHSPC) or metastatic castration resistant prostate cancer (mCRPC), for whom ARPI in combination with androgen deprivation is clinically planned 3. Prior ADT use for prostate cancer (including bilateral orchidectomy and transcutaneous oestrogen), is permitted provided: (a) ADT has been started less than 12 weeks prior to randomisation in mHSPC, (b) In the adjuvant setting the completion of adjuvant hormonal therapy was \>12 months prior to randomisation and total duration is capped at 36 months total 4. ECOG performance status 0-2 5. Willing and able to give provide written informed consent. Exclusion Criteria: 1. Pathology other than adenocarcinoma consistent with small cell, ductal, sarcomatoid carcinoma of the prostate 2. Unable or unwilling to receive concurrent ADT alongside an ARPI 3. Any concurrent or previous malignancy that required active anti-cancer therapy in the previous 2 years of randomisation (other than basal cell or squamous cell carcinoma of the skin or adequately treated non-muscle invasive urothelial bladder carcinoma, Tis, Ta and T1 tumours) 4. Adults with unmanaged psychological, familial, or sociological conditions precluding them from the ability to provide informed consent or hampering compliance with the study follow-up, including continued drug and alcohol dependence 5. Patients who have received an investigational drug (either approved or not approved) in any prior clinical study within 30 days or 5 half-lives (whichever is longer) prior to Screening 6. Patients on triplet therapy (i.e. receiving additional systemic anti-cancer therapy such as chemotherapy, radionuclide/molecular radiotherapy, PARPi alongside ADT \& ARPI); but concomitant radiotherapy is allowed 7. Hypersensitivity to any of the active components or excipients of the IMPs or NIMPs listed in this protocol 8. Patients with severe hepatic impairment (Child-Pugh Class C) 9. Patients with uncontrolled or unstable cardiovascular disease, New York Heart Association congestive cardiac failure class III/IV

Outcomes

Primary Outcomes

Overall survival (primary efficacy)

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: 1. Non-inferiority for overall survival 2. Superiority of a mean difference in QoL fatigue score (expected to be ≥7 units) 3. Superiority for the percentage of patients who do not discontinue ARPI due to adverse events

Time frame: From randomisation up to 6 years (or date last known to be alive) or date of death, whichever occurs first.

The percentage of patients who permanently 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: 1. Non-inferiority for overall survival 2. Superiority of a mean difference in QoL fatigue score (expected to be ≥7 units) 3. Superiority for the percentage of patients who do not discontinue ARPI due to adverse events

Time frame: From start of treatment to permanent discontinuation of trial treatment up to 3 years after last patient is recruited (approximately 6 years for the first patient recruited).

Fatigue assessed using the EORTC 12-point fatigue scale (primary toxicity)

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: 1. Non-inferiority for overall survival 2. Superiority of a mean difference in QoL fatigue score (expected to be ≥7 units) 3. Superiority for the percentage of patients who do not discontinue ARPI due to adverse events

Time frame: Pre-treatment, Weeks 16, 32, 48 and 64 from start of treatment.

Secondary Outcomes

Toxicities using the CTCAE v6 categorisation (all grades).

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.

Time frame: From date of consent to 30 days post last IMP dose administration.

Failure-free survival (FFS)

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.

Time frame: From randomisation until disease progression or death up to 6 years after first patient enrolled.

Measures of progression (rising PSA, and locally defined clinical and radiological progression), at 1 and 2 years post-randomisation.

* 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).

Time frame: From randomisation to date of documented objective disease progression, assessed up to 2 years post-randomisation.

Adherence: the proportion of patients who stop ARPI permanently due to reasons other than disease progression, at 1 and 2 years.

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

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

Time frame: From start of treatment to documented dose reduction of trial treatment due to adverse events up to 3 years after last patient is recruited (approximately 6 years for the first patient recruited).

Health-related quality of life using the EORTC QLQ-C30 questions

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.

Time frame: Pre-treatment, Weeks 16, 32, 48 and 64 from start of treatment.

Health-related quality of life using the EORTC QLQ-IL249 questions

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.

Time frame: Pre-treatment, Weeks 16, 32, 48 and 64 from start of treatment.

Health-related quality of life using the Euro-Qol-5D-5L (EQ-5D-5L)

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.

Time frame: Pre-treatment, Weeks 16, 32, 48 and 64 from start of treatment.

Evaluating Hormone Therapy to Achieve Optimal Doses in Metastatic Prostate Cancer

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts