PROstate Cancer TReatment Optimization Via Analysis of Circulating Tumour DNA

Study Overview
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Brief Summary
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The purpose of this study is to assess the strategy in treatment selection using ctDNA fraction as a predictive biomarker to direct treatment decision (ctDNA fraction <2% receives enzalutamide, and ctDNA fraction ≥2% receives docetaxel) versus clinician's choice of enzalutamide or docetaxel, in subjects with metastatic castration-resistant prostate cancer post abiraterone setting.

Detailed Description
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This is a prospective, open-label, phase II trial with 1:1 randomization to either Arm A biomarker directed therapy (patients with ctDNA fraction <2% receive enzalutamide, and ctDNA fraction ≥2% receive docetaxel), versus Arm B clinician's choice of enzalutamide or docetaxel, in subjects with metastatic castration-resistant prostate cancer post abiraterone. At time of progression, patient will cross-over to the other therapy (e.g., enzalutamide to docetaxel, and docetaxel to enzalutamide).

Official Title
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A Randomized Phase II Trial Comparing Biomarker Directed Therapy Versus Clinician's Choice of Enzalutamide or Docetaxel in Patients With Advanced Prostate Cancer Post Abiraterone

Conditions
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Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Intervention / Treatment
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* Drug: Enzalutamide
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Patients must meet ALL of the following criteria: Willing and able to provide informed consent Adult males ≥ 18 years age History of histologically confirmed adenocarcinoma of the prostate without evidence of neuroendocrine or small cell differentiation. If histology is not available, patients must have metastatic disease typical of prostate cancer (i.e., involving bone or pelvic lymph nodes or para-aortic lymph nodes) AND a serum concentration of PSA that is rising and >20ng/mL at the time prostate cancer was diagnosed clinically Consent to analysis of archival tissue collected at diagnosis is mandatory Prior surgical orchiectomy or if on LHRH agonist/antagonist then testosterone < 1.7 nmol/L at screening visit (patients must maintain LHRH agonist/antagonist therapy for duration of study treatment if not surgically castrated) Evidence of metastatic disease on bone scan or CT scan Evidence of biochemical or imaging progression in the setting of surgical or medical castration while on abiraterone. Progressive disease for study entry is defined by one of the following three criteria as per PCWG317: PSA progression: minimum of two rising PSA values from a baseline measurement of one week interval. Minimum PSA at screening visit is 1.0 ng/mL Soft tissue or visceral disease progression: an increase ≥20% in the sum of the diameter (short axis for nodal lesions and long axis for non-nodal lesions) from the smallest sum of the diameter since treatment started, or appearance of any new lesions (see Appendix B for definition of measurable disease as per RECIST 1.1 criteria). Bone progression: ≥ 2 new lesions on bone scan confirmed on subsequent bone scan at least 8 weeks apart (2+2 rule as per PCWG317) ECOG performance status 0-2 (see Appendix C) Prior treatment with abiraterone, in either castration-sensitive or castration-resistant setting. Eligible for treatment with either enzalutamide or docetaxel as per standard of care guidelines Adequate organ function defined as: Absolute neutrophil count ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L and hemoglobin ≥ 90 g/L Creatinine clearance ≥ 30 ml/min (calculated by Cockcroft-Gault formula, see Appendix D) Total bilirubin ≤ 1.5 x upper limit of normal (ULN) except for patients with known Gilbert's syndrome (direct bilirubin ≤ 1.5 x ULN) Alanine aminotransferase (ALT) ≤ 5 x ULN Able to swallow study drug and comply with study requirements including provision of peripheral blood samples at specified time points for correlative studies Recovery from all prior treatment-related toxicity to grade ≤ 2 (as per CTCAE 5.0) EXCLUSION CRITERIA Patients must NOT meet any of the following criteria: Severe concurrent illness or co-morbid disease that would make the subject unsuitable for enrolment Prior therapy with enzalutamide or other experimental anti-androgens (e.g. ARN-509, TOK-001) Prior systemic chemotherapy with docetaxel or cabazitaxel (with the exception of: patients who were treated with docetaxel for castration sensitive disease and did not progress for at least 12 months after completion of docetaxel) Active concurrent malignancy (with the exception of non-melanomatous skin cancer, or other solid tumours curatively treated with no evidence of disease for ≥3 years) Wide-field radiotherapy or radioisotopes such as Strontium-89, or Radium-223 ≤ 28 days prior to starting study drug (limited-field palliative radiotherapy for up to 5 fractions prior to starting study drug is permitted) Brain metastases or active epidural disease (treated epidural disease is permitted) Contraindication to prednisone therapy including poorly controlled diabetes mellitus History of seizure or seizure disorder, or history of any cerebrovascular event within 6 months of study entry. Uncontrolled hypertension Grade ≥3 (i.e. systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg) Gastrointestinal disorder affecting absorption Major surgery within 4 weeks of starting study treatment

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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A: Biomarker directed Therapy (BT)<br>ctDNA fraction <2% receives enzalutamide, and ctDNA fraction ≥2% receives docetaxel until disease progression, then cross-over to the other therapy (e.g., enzalutamide to docetaxel, or docetaxel to enzalutamide). | Drug: Enzalutamide<br>* Enzalutamide 160 mg PO OD<br>* Other names: Xtandi;Drug: Docetaxel<br>* Docetaxel 75 mg/m2 IV every 3 weeks<br>* Other names: Taxotere;|
| Active Comparator: B: Clinician's Choice (CC)<br>Enzalutamide or docetaxel until disease progression, then cross-over to the other therapy (e.g., enzalutamide to docetaxel, or docetaxel to enzalutamide). | Drug: Enzalutamide<br>* Enzalutamide 160 mg PO OD<br>* Other names: Xtandi;Drug: Docetaxel<br>* Docetaxel 75 mg/m2 IV every 3 weeks<br>* Other names: Taxotere;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | PFS is defined as the time between the date of starting trial treatment to any of the following: clinical, PSA, radiographic progression, or death from any cause on first-line therapy | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response | To determine the objective response as per RECIST 1.1 in patients treated with biomarker directed therapy vs. clinician's choice. | 1 year | 
| PSA response rate | PSA response rate is defined as the proportion of patients with a PSA decline (defined as a ≥30%, ≥50% and other declines in PSA from baseline) in mCRPC patients treated with biomarker directed therapy vs. clinician's choice. | 1 year | 
| Second progression free survival (PFS2) | PFS2 is defined as the time elapsed between the date of treatment commencement and the first documented evidence of any disease progression or death from any cause from cross-over second-line therapy. | 1 year | 
| Overall survival (OS) | OS is defined as time from treatment commencement to death of any cause of mCRPC patients treated with biomarker directed therapy vs. clinician's choice. | 2 years | 
| Clinical benefit rate (CBR) | CBR is defined as PSA or measurable radiological response of any duration or stable disease for ≥ 12 weeks (no symptomatic progression, PSA progression, or objective disease progression). | 3 months | 
| Correlation of specific ctDNA-based genomic alterations to treatment response | Among mCRPC patients receiving enzalutamide and docetaxel | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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circulating tumor DNA, Enzalutamide, Docetaxel