Overview
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.
Description
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:
- LHRHa + APA for 16 weeks or
- 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:
- LHRHa + AAP for 16 weeks or
- 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:
- LHRHa + APA plus PD-L1 inhibitor (atezolizumab) for 16 weeks
Eligibility
Inclusion Criteria:
- I. Males ≥ 18 years of age
II. Histologically confirmed adenocarcinoma of the prostate without pathologic evidence of
small cell differentiation at the time of initial diagnosis
III. High-risk localized prostate cancer as defined by:
- PSA (prostate specific antigen) >20, any GS or >8 or
- Gleason pattern 4 in 6 or more systematic cores (pattern 4 must be dominant, ≥50%
average across 6 or more systematic cores) or
- ≥ 50% Gleason pattern 4 in 3 or more systematic or Magnetic Resonance Imaging
(MRI)-targeted cores and PSA ≥ 20 (may include G4+3 or G4+4 but pattern 4 must be
dominant, ≥50% average across 3 or more systematic cores) or
- ≥25% Gleason pattern 5 in 3 or more systematic or MRI-targeted cores (may include
G4+5, or G3+5, but pattern 5 must be ≥25% average across 3 or more systematic cores).
- Gleason > 8 or greater on minimum of one core either targeted or systematic biopsy and
PSA >20
- Participants with oligometastatic (< 3) metastases by PSMA (Prostate-Specific Membrane
Antigen) imaging only who are deemed candidates for radical prostatectomy are eligible
IV. Participants must consent to genetic testing at registration and prior to assignment by
a central reference laboratory
V. No prior systemic or localized treatment for prostate cancer. Up to 30 days of LHRHa is
allowable prior to treatment.
VI. ECOG (Eastern Cooperative Oncology Group) performance status 0 or 1 (Appendix II) and a
life expectancy of ≥ 3 years
VII. Participants must have adequate end-organ function and all laboratory tests must be
performed within 4 weeks prior to registration into master protocol.
VIII. Participant consent must be appropriately obtained in accordance with applicable
local and regulatory requirements. Each participant must sign a consent form prior to
enrolment in the trial to document their willingness to participate.
Exclusion Criteria:
- I. Received more than 30 days of LHRHa prior to registration and initiation of LHRHa +
APA
II. Stage T4 prostate cancer by clinical examination or radiologic evaluation
III. Hypogonadism or severe androgen deficiency as defined by screening serum testosterone
more than 50 ng/dL below the normal range for the institution
IV. Participants with serious illnesses or medical conditions which could cause
unacceptable safety risks or would not permit the participant to be managed according to
the protocol. This includes but is not limited to:
- Active infection or chronic liver disease requiring systemic therapy;
- Active or known human immunodeficiency virus (HIV) with detectable viral load;
- Uncontrolled or recent clinically significant cardiac disease, including: angina
pectoris, symptomatic pericarditis, coronary artery bypass grafting, coronary
angioplasty, or stenting, or myocardial infarction in the previous 12 months; history
of documented congestive heart failure (New York Heart Association functional
classification III-IV) or cardiomyopathy; history of any cardiac arrhythmias, e.g.
ventricular, supraventricular, nodal arrhythmias, or conduction abnormality in the
previous 12 months;
- Participants with uncontrolled hypertension
V. Participants who are unable to swallow oral medication and/or have impairment of
gastrointestinal (GI) function or GI disease that may significantly alter the absorption of
the study drugs (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea,
malabsorption syndrome, or small bowel resection)
VI. Participants with a history of hypersensitivity to any of the study drugs or any
excipient
VII. Participants with a history of non-compliance to medical regimen
VIII. Severe concurrent disease, infection, or co-morbidity that, in the judgement of the
Investigator, would make the participant inappropriate for enrollment or prostatectomy
IX. Prior androgen deprivation, chemotherapy, surgery, or radiation for prostate cancer
X. Receiving concurrent androgens, estrogens, or pregestational agents, or prior exposure
to any of these agents within 6 months prior to randomization
XI. M1 by conventional imaging (CT, bone scan)