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

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: 1. LHRHa + APA plus PD-L1 inhibitor (atezolizumab) for 16 weeks * This arm is closed to enrollment Sub-Protocol 5 - cancers primed for lineage plasticity: Loss of function DNA alteration in TP53 or RB1 and/or evidence of stem cell or neuroendocrine (NE) features (\~20%) assigned to: a. LHRHa + AAP + tazemetostat for 16 weeks \*\*\*This arm is closed to enrollment Sub-protocol 6 - favorable genomic alterations as defined in SP-1, or PTENdef/AKTgain alterations (20%), will be assigned to SP-6a and SP-6b respectively, and receive a. LHRHa + AAP + capivasertib (CAPIVA) for 16 weeks