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Genital Diseases, Male

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Male Urogenital Diseases

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Niraparib

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LHRHa plus apalutamide plus abiraterone acetate plus prednisone.

LHRHa plus abiraterone acetate plus prednisone.

LHRHa plus abiraterone acetate plus prednisone plus docetaxel.

LHRHa plus abiraterone acetate plus prednisone plus niraparib

4 tablets by mouth once a day for 24 weeks

Apalutamide 60mg Tab

4 tablets by mouth on an empty stomach once a day for 16 weeks

Abiraterone Acetate 250mg

1 tablet by mouth once daily while taking abiraterone acetate

Prednisone 5mg Tab

Infusion every 3 weeks for 6 cycles (each cycle has 3 weeks)

3 capsules by mouth once daily for 16 weeks

Niraparib 100mg Oral Capsule

1200mg infusion every 3 weeks for 6 cycles

Martin E Gleave, MD

Miran Kenk, PhD

Anthony Martinez

Marc Dall'Era, MD

Mamta Parikh, MD

Daniella Furtado

Adam Kibel, MD

Lindsay Sazkaly

Todd Morgan, MD

askMDAnderson

Brian Chapin, M.D.

Jonathan Ma

Pascale Juneau

Rodney Breau, MD

Anuja Parikh, HBSc

Neil Fleshner, M.D.

The objective of this study is to see if providing an appropriate therapy based on the genomic testing of prostate tumour tissue will result in an improved clinical response.

Each participant will be treated with 8 weeks of a luteinizing hormone-releasing hormone agonist (LHRHa) plus apalutamide (APA) while genome sequence characterization is being done. Participants with biopsy specimens deemed unevaluable for genomic testing will remain on LHRHa plus APA for an additional 16 weeks.

Participants with evaluable tissue will be assigned to one of the open-label sub-studies on the basis of genomic profiling results. Within each group, they will be randomized to a specific treatment arm either LHRHa plus APA alone or adding abiraterone acetate and prednisone, docetaxel or niraparib.

The study will evaluate the response rate and outcomes after radical prostatectomy in each arm of the trial.

This is a multi-centre adaptive multi-arm phase II study. Participants are treated with an induction period of at least 8 weeks of LHRH agonist/antagonist (LHRHa) plus apalutamide (APA) while genome sequence characterization is being done.

Genomic sequencing analysis will be performed centrally by Tempus, a CLIA (Clinical Laboratory Improvement Amendments)-certified laboratory. For the DNA gene profiling, formalin-fixed paraffin-embedded (FFPE) prostate cancer and surrounding healthy tissue from diagnostic biopsies will be used for genetic analysis. Copy number profiling will be performed using array Comparative Genomic Hybridisation (aCGH). Targeted sequencing using MiSeq (Illumina) and Ion Proton (Life Technologies) platforms will be performed to identify mutations in a panel of 648 genes.

Based on previous studies, we conservatively expect up to 25% of unevaluable needle biopsy specimens with inadequate/insufficient tumor tissue for genome sequencing. The patients with unevaluable tissue will continue on the master protocol (LHRHa + APA) for an additional 16 weeks followed by radical prostatectomy.

The genomically evaluable patients will be assigned to a specific sub-protocol according to the results of the genomic profile and randomized to a treatment arm within the sub-protocol for 16 weeks, with additional inclusion and exclusion criteria specified in dedicated sub-protocols. Radical prostatectomy will follow sub-protocol treatment.

Sub-protocol 1 - AR axis: No targetable actionable aberration; presence of TMPRSS2-ERG fusion, CHD1 loss or SPOP mutations: (\~50% expected prevalence in study population) randomized to:

1. LHRHa + APA for 16 weeks or
2. LHRHa + APA + AAP (Abiraterone Acetate + Prednisone) for 16 weeks

Sub-protocol 2 - Loss of tumour suppressor genes - PTEN, TP53 or TB loss (\~40%, bad prognosis) randomized to:

1. LHRHa + AAP for 16 weeks or
2. LHRHa + AAP + docetaxel for 6 cycles

Sub-protocol 3 - DNA damage response alterations (e.g. BRCA1/2, ATM, FANCONI, CDK12) in 6-8% assigned to:

* LHRHa + AAP + PARP (Poly \[ADP-ribose\] polymerase) inhibitors (niraparib) for 16 weeks

Sub-protocol 4 - Hypermutation, microsatellite instability (MSI), Lynch syndrome or CDK12 in less than 5% assigned to:

a. LHRHa + APA plus PD-L1 inhibitor (atezolizumab) for 16 weeks

Genomic Biomarker-Selected Umbrella Neoadjuvant Study for High Risk Localized Prostate Cancer

Pathological Minimal Residual Disease (pMRD): pathological minimal residual disease (pMRD) is defined as residual tumour 5mm or less.

Pathological minimal residual disease is defined as residual tumour 5 mm or less.

The Brief Pain Inventory-Short Form (BPI-SF) is a 9-item, self administered questionnaire which evaluates the severity of a participant's level of pain and impact on daily functioning. This questionnaire will be administered at screening, prior to receiving master protocol therapy (0 weeks), the end of receiving therapy (8 weeks), as well as the End of Treatment (EoT) visit.

The EQ-5D-5L is a widely used instrument developed in Europe to evaluate the generic quality of life. The EQ-5D-5L has two components: the EQ-5D descriptive system and the EQ visual analogue scale. This questionnaire will be administered at screening, prior to receiving master protocol therapy (0 weeks), the end of receiving therapy (8 weeks) as well as at the EoT visit.

This will be measured using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. The FACT-P is a multidimensional, self-report QoL instrument specifically designed for use with patients who have prostate cancer. This questionnaire will be administered at screening, prior to receiving master protocol therapy (0 weeks), the end of receiving therapy (8 weeks) as well as at the EoT visit.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Genomic Biomarker-Selected Umbrella Neoadjuvant Study for High Risk Localized Prostate Cancer	NCT04812366	Prostate Cancer	Apalutamide 60m... Abiraterone Ace... Prednisone 5mg ... Docetaxel Niraparib 100mg... Atezolizumab	18 Years -	University of British Columbia
Genomic Biomarker-Selected Umbrella Neoadjuvant Study for High Risk Localized Prostate Cancer	NCT04812366	Prostate Cancer	Apalutamide 60m... Abiraterone Ace... Prednisone 5mg ... Docetaxel Niraparib 100mg... Atezolizumab	18 Years -	University of British Columbia

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