Molecular Stratification Profiling Protocol in Metastatic Castration Resistant Prostate Cancer (mCRPC) - MAESTRO

Study Overview
=================
Brief Summary
-----------------
This study is a prospective, observational, molecular stratification profiling study. Patients with mCRPC who have received at least one standard treatment for mCRPC will be approached to participate in MAESTRO. Patients must have archival tumour available and be willing to undergo a fresh tumour biopsy for molecular analyses. Tumour tissue (archival and fresh), research blood samples and saliva will be sent to the central laboratory for analysis to identify molecular aberrations through targeted or broader molecular analyses (e.g. exome, transcriptome) and orthogonal assays (e.g. immunohistochemistry; digital droplet PCR). When the results are available, depending on patients choice, the results will be discussed. If significant results are indicated, patients will be recommended to have follow up with a cancer geneticist to discuss the implications of these results for their personal and family's health. There is a safety follow up 30 days after collection of study biopsy or blood samples. Patients will also be followed up for overall survival and subsequent anticancer treatment every 6 monthly via medical notes or telephone calls.

Detailed Description
-----------------
This study is a prospective, observational, molecular stratification profiling study. mCRPC patients who have received at least one standard treatment for mCRPC will be approached to participate in MAESTRO. Patients must have archival tumour available and be willing to undergo a fresh tumour biopsy for molecular analyses. Following consent to MAESTRO, tumour tissue (archival and fresh), along with the research blood samples and saliva sample will be sent to the central laboratory for analysis to identify molecular aberrations through targeted or broader genomic analyses (e.g. exome, transcriptome) and orthogonal assays (e.g. immunohistochemistry; digital droplet PCR). Patients will not receive any treatment as part of MAESTRO. Results of the molecular characterisation will be provided to the treating investigator to be fed back to the patient, depending on patient's choice on disclosing the results. The following research samples are collected under as part of this study: Where available, excess archival tumour tissue from previous biopsies or routine surgical procedures will be retrospectively collected. Fresh tissue specimens will be obtained for patients who are undergoing standard of care interventions OR patient will undergo a bone marrow biopsy or an ultrasound /CT guided tumour biopsy of a safely accessible lesion. Fresh tumour specimens will be processed and/or frozen. Sequencing analysis of tissues will be done and results will be made available in real time. Clinically significant results will be disclosed to patients and their clinicians as per patient consent. Research samples for blood, serum, plasma and saliva will be collected at the time of the biopsy. Patients who elected (optional consent) to receive sequencing results regarding incidental clinically significant findings, will be referred for genetic counselling.

Official Title
-----------------
MAESTRO: Molecular Stratification Profiling Protocol in Metastatic Castration Resistant Prostate Cancer (mCRPC)

Conditions
-----------------
Metastatic Prostate Cancer, Castration-resistant Prostate Cancer

Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male aged ≥18 years. Histologically confirmed metastatic castrate resistant adenocarcinoma of the prostate Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 - 2. Surgically or medically castrated, with testosterone levels of <50 ng/dL (<2.0 nM). Confirmed metastatic disease on imaging. Patients with tumour deemed by the designated investigator as safely suitable for fresh biopsy AND who are medically fit (according to local practice) to undergo a biopsy or procedure to acquire tumour tissue AND previously collected tumour specimens from prior surgery or biopsy available for analyses. An mCRPC biopsy collected within 6-months of trial entry can be used instead of this fresh biopsy if available and passes laboratory quality control requirements. Willing and able to comply with the requirements of the sample collection including fresh tumour biopsy. The subject is capable of understanding and complying with the protocol requirements and has given written informed consent. Exclusion Criteria: The presence of any haematological disorders, including coagulation disorders, which would be a contraindication if patient were to undergo a biopsy. Any psychiatric illness/social situations that would limit compliance with study requirements. Presence of any concurrent condition or situation, which, in the investigators opinion, may put the patient at significant risk, may confound the study results or may interfere significantly with the patient's participation in the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------
What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of molecular aberrations in diagnostic archive and fresh mCRPC tissue | The prevalence of molecular aberrations in diagnostic archive and fresh mCRPC will be calculated with 95% confidence intervals. | 4-6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantify the association between molecular aberrations and baseline prognostic characteristics | The association between identified molecular aberrations and baseline characteristics, known to be prognostic factors, will be quantified. Associations will be determined using Fisher's exact test for categorical characteristics and for continuous characteristics either a Wilcoxon rank sum test or t test will be used depending on the results of normality testing. | 4-6 weeks | 
| Changes in molecular aberrations | Changes in the molecular features of tumour biopsies acquired at diagnosis and fresh mCRPC will be quantified to demonstrate any differences in the molecular aberrations within the same patient's tumour. | 4-6 weeks | 
| Safety - Review of biopsy-related adverse events: occurrence of at least one grade 3 or 4 event | All events experienced by patients related to study procedures (collection of a fresh biopsy or blood samples) will be recorded and graded using CTCAE version 5 criteria and specifically the occurrence of at least one grade 3 or 4 event. Adverse events will be summarised by grade according to the worst grade experienced. In addition, the most frequently observed AEs will be summarised. The overall proportion of patients experiencing at least one grade 3 or 4 event will be presented by study procedure. | 30 days after study biopsy/blood collection | 
| Time to development of CRPC | This is defined in whole days as the time from the date of diagnosis to the date of confirmed CRPC. The median time and interquartile range will be determined per molecular aberration. Analyses will be conducted per molecular aberration and will use the Kaplan-Meier method and Cox proportional hazard models. Analyses will adjust for known baseline characteristics and previous treatments received using multivariable Cox proportional hazard models. | From the date of diagnosis to the date of confirmed mCRPC, through study completion, up to 5 years | 
| Overall Survival (OS) | OS will be measured from the date of CRPC to the date of death (whatever the cause). Survival time of living patients will be censored on the last date a patient is known to be alive or lost to follow-up. Analyses will use the Kaplan Meier method and Cox proportional hazard models by molecular aberration. Multivariable Cox proportional hazard models will include established prognostic factors such as site of disease. | From the date of confirmed CRPC to the date of death from any cause, , through study completion, up to 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
prostate, molecular stratification