TherApeutics in Early ProState Cancer (TAPS02)

Study Overview
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Brief Summary
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This is a phase 3, randomised, multicentre, double-blind, placebo-controlled trial investigating the use of short term androgen deprivation therapy in the form of apalutamide (Erleada) in men on active surveillance for prostate cancer.

Official Title
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Targeted Drug Intervention in Men at Risk of Progression on Active Surveillance for Early Prostate Cancer: A Randomised Trial - Therapeutics in Active Prostate Cancer Surveillance (TAPS02).

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Apalutamide Oral Tablet [Erleada]
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA To be included in the trial the patient must: Have given written informed consent to participate. Be aged 18 or over. Have an Eastern Cooperative Oncology Group (ECOG) status 0-2. Have selected active surveillance as a management option. Have an MRI detectable lesion with an M score of ≥ 3 using Likert scale OR PIRADS (version 2.1) reporting criteria. If M score is 3 then lesion size (single or combined) of ≥10mm. Have prostate cancer from a combination of image guided targeted + systematic biopsies and MRI lesion and biopsy are concordant for a prostate cancer diagnosis. Not anticipated to require bladder outlet surgery during IMP treatment or for up to 12 months of follow-up. Meet all of the following clinical laboratory assessment criteria: Haemoglobin ≥ 9.0 g/dL, independent of transfusion and/or growth factors within 3 months prior to randomisation. Platelet count ≥ 100 x 109/L independent of transfusion and/or growth factors within 3 months prior to randomisation. Absolute neutrophil count (ANC) ≥ 1.0 x 109/L within 21 days prior to randomisation. Serum albumin ≥ 3.0 g/dL within 21 days prior to randomisation. Glomerular filtration rate (GFR) ≥ 30 ml/min AND Serum creatinine ≤ 3 times the ULN (calculated by Cockcroft and Gault equation using actual body weight) within 21 days prior to randomisation. Serum potassium ≥3.5 mmol/L within 21 days prior to randomisation. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤2.5 × ULN AND Serum total bilirubin ≤1.5 × ULN within 21 days prior to randomisation (Note: In patients with confirmed Gilbert's syndrome, if total bilirubin is >1.5 × ULN, measure direct and indirect bilirubin and if direct bilirubin is ≤1.5 × ULN, patient may be eligible in consultation with their physician). Have prostate cancer with any one or more of the following: CPG2 (based on Grade Group 2 on histology) CPG1 (based on Grade Group 1 on histology) with PSA high density (PSAd >0.15) and LIKERT or PIRADS 4/5 lesion (individual or combined) of ≥10mm size. CPG1 with PSA high density (PSAd >0.15) and ≥50% biopsy core involvement (number of positive cores/all cores taken) with target biopsies counted as one if LIKERT or PIRADS 3 lesion EXCLUSION CRITERIA The presence of any of the following will preclude patient inclusion: Contraindications to apalutamide or its excipients. Pelvic metalwork interfering with MRI prostate interpretation. Any prior or concurrent use of androgen deprivation therapy (ADT) or androgen receptor targeting agents (not including established and continued use of 5-ARIs for urinary symptoms). Systemic therapy for prostate cancer. No concurrent use of any other ADT. Inability for patient to have prostate MRI scan. Concurrent involvement in a Clinical Trial of Investigational Medicinal Product (CTIMP); participation in an observational trial/studies is acceptable. Seizure or known condition that may pre-dispose to seizure (including but not limited to the following within 1 year prior to randomisation: prior stroke, transient ischemic attack, loss of consciousness, brain arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas that are causing oedema or mass effect). Medications known to lower the seizure threshold or cause seizures must be discontinued or substituted at least 28 days prior to randomisation. Patient has history/is at risk of falls/fracture. Severe/unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias within 6 months prior to randomisation. Cardiovascular risk factors should be optimised i.e. hypertension, diabetes, dyslipidaemia. Uncontrolled hypertension (SBP ≥ 160 mmHg or DBP ≥ 90 mmHg). Patients with a history of uncontrolled hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment. Gastrointestinal disorder affecting absorption. Medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes such as class IA (e.g., quinidine, disopyramide) or class III (e.g., amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics (e.g. haloperidol), etc. should be carefully evaluated. Symptoms suggestive of Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The trial will occur in two stages. Following an initial 3-arm Pilot stage, a go-no go decision will be made. If successful, the trial will progress and adapt to become a 2-arm trial in the subsequent stage.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Apalutamide 6 months<br>Participants will receive apalutamide 240 mg (4 x 60 mg tablets) orally once a day for up to 6 months. | Drug: Apalutamide Oral Tablet [Erleada]<br>* Apalutamide is a selective Androgen Receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR.<br>* Other names: Erleada;|
| Experimental: Apalutamide 3 months + Placebo 3 months<br>Participants will receive apalutamide 240mg (4 x 60 mg tablets) orally once a day for up to 3 months followed by placebo to match apalutamide (4 tablets) orally once a day for up to 3 months. | Drug: Apalutamide Oral Tablet [Erleada]<br>* Apalutamide is a selective Androgen Receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR.<br>* Other names: Erleada;|
| Placebo Comparator: Placebo 6 months<br>Participants will receive placebo to match apalutamide (4 tablets) orally once a day for up to 6 months. | Drug: Placebo<br>* Placebo to match apalutamide<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MRI defined tumour volume (Pilot) | To determine whether there is a reduction in MRI defined tumour volume at 12 months post treatment in at least 50% of the treated cohort in either treatment arm compared to the baseline measurement. | 12 months after end of treatment | 
| Cumulative rate of disease progression (Full Trial) | To determine whether there is a 50% reduction in cumulative 3-year progression rate to ≥ Grade Group 3 or T3 stage and composite score of ≥ CPG3 disease. | 3 years after completion of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reported adverse events (Pilot) | As per NCI-CTCAE v5.0 | Reported from the point of obtaining informed consent until the safety FU visit (30-45 days post-treatment) | 
| Patient-reported outcomes (Pilot) | Assessed using the European Organisation for Research and Treatment of Cancer Quality of Life of Cancer Patients questionnaire (EORTC-QLQC30). | Cumulative until 12 months after end of treatment | 
| Patient-reported outcomes (Pilot) | Assessed using the EQ-5D-5L questionnaire developed by the EuroQol Group. | Cumulative until 12 months after end of treatment | 
| Reported adverse events (Full Trial) | As per NCI-CTCAE v5.0 | Reported from the point of obtaining informed consent until the safety FU visit (30-45 days post-treatment) | 
| Patient-reported outcomes (Full Trial) | Assessed using the European Organisation for Research and Treatment of Cancer Quality of Life of Cancer Patients questionnaire (EORTC-QLQC30). | Cumulative until 3 years after completion of treatment | 
| Patient-reported outcomes (Full Trial) | Assessed using the EQ-5D-5L questionnaire developed by the EuroQol Group. | Cumulative until 3 years after completion of treatment | 
| Cumulative rate of progression (any progression) (Full Trial) |  | 3 years after completion of treatment | 
| Cumulative rate of progression to radical treatment (for any cause) (Full Trial) |  | 3 years after completion of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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active surveillance, prostate cancer, therapeutics in prostate cancer, apalutamide, short term androgen deprivation therapy, androgen receptor inhibitor