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

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.

Study Overview

• Status: Recruiting
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: Apalutamide 60mg Tab; Drug: Abiraterone Acetate 250mg; Drug: Prednisone 5mg Tab; Drug: Docetaxel; Drug: Niraparib 100mg Oral Capsule; Drug: Atezolizumab

Detailed 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:

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

• Study Type: Interventional
• Enrollment (Estimated): 315
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Martin E Gleave, MD; Phone Number: 604-875-5006; Email: m.gleave@ubc.ca
• Study Contact Backup: Name: Tiiu Sildva, PhD; Email: tiiu.sildva@uhn.ca

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Recruiting
      • Vancouver Prostate Centre
      • Contact: Jonathan Ma; Phone Number: 16048755675; Email: jma@prostatecentre.com
      • Contact: Martin E Gleave, MD
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • Recruiting
      • London Health Sciences Centre
      • Contact: Wendy Shoff; Phone Number: 57350 519-685-8500; Email: wendy.shoff@lhsc.on.ca
      • Contact: Brant Inman, MD
    • Ottawa, Ontario, Canada, K1H 8L6
      • Recruiting
      • Ottawa Hospital Research Institute (OHRI)
      • Contact: Pascale Juneau; Phone Number: 71064 613-737-8899; Email: pjuneau@ohri.ca
      • Contact: Rodney Breau, MD
    • Toronto, Ontario, Canada, M5G 2C4
      • Recruiting
      • University Health Network
      • Contact: Anuja Parikh, HBSc; Phone Number: 5981 416-946-4501; Email: Anuja.Parikh@uhn.ca
      • Contact: Neil Fleshner, M.D.
• United States
  • California
    • Sacramento, California, United States, 95817
      • Recruiting
      • University of California Davis
      • Contact: Anthony Martinez; Phone Number: 916-734-0162; Email: axmartinez@ucdavis.edu
      • Contact: Marc Dall'Era, MD
      • Contact: Mamta Parikh, MD
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Brigham & Women's Hospital
      • Contact: Daniella Furtado; Phone Number: 617-525-8782; Email: Daniella_Furtado@dfci.harvard.edu
      • Contact: Adam Kibel, MD
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-5946
      • Recruiting
      • University of Michigan Health
      • Contact: Lindsay Sazkaly; Phone Number: 734-936-7699; Email: lszakaly@med.umich.edu
      • Contact: Todd Morgan, MD
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • U.T. MD Anderson Cancer Center
      • Contact: askMDAnderson; Phone Number: 877-632-6789; Email: askmdanderson@mdanderson.org
      • Contact: Brian Chapin, M.D.
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • Fred Hutchinson Cancer Center
      • Contact: Amanda Bard; Phone Number: 2066674519
      • Contact: Michael Schweizer, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group 1a; LHRHa plus apalutamide.	Drug: Apalutamide 60mg Tab; 4 tablets by mouth once a day for 24 weeks
Active Comparator: Group 1b; LHRHa plus apalutamide plus abiraterone acetate plus prednisone.	Drug: Apalutamide 60mg Tab; 4 tablets by mouth once a day for 24 weeks; Drug: Abiraterone Acetate 250mg; 4 tablets by mouth on an empty stomach once a day for 16 weeks; Drug: Prednisone 5mg Tab; 1 tablet by mouth once daily while taking abiraterone acetate
Active Comparator: Group 2a; LHRHa plus abiraterone acetate plus prednisone.	Drug: Abiraterone Acetate 250mg; 4 tablets by mouth on an empty stomach once a day for 16 weeks; Drug: Prednisone 5mg Tab; 1 tablet by mouth once daily while taking abiraterone acetate
Active Comparator: Group 2b; LHRHa plus abiraterone acetate plus prednisone plus docetaxel.	Drug: Abiraterone Acetate 250mg; 4 tablets by mouth on an empty stomach once a day for 16 weeks; Drug: Prednisone 5mg Tab; 1 tablet by mouth once daily while taking abiraterone acetate; Drug: Docetaxel; Infusion every 3 weeks for 6 cycles (each cycle has 3 weeks)
Active Comparator: Group 3; LHRHa plus abiraterone acetate plus prednisone plus niraparib	Drug: Abiraterone Acetate 250mg; 4 tablets by mouth on an empty stomach once a day for 16 weeks; Drug: Prednisone 5mg Tab; 1 tablet by mouth once daily while taking abiraterone acetate; Drug: Niraparib 100mg Oral Capsule; 3 capsules by mouth once daily for 16 weeks
Active Comparator: Group 4; LHRHa plus apalutamide plus atezolizumab	Drug: Apalutamide 60mg Tab; 4 tablets by mouth once a day for 24 weeks; Drug: Atezolizumab; 1200mg infusion every 3 weeks for 6 cycles

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Pathologic Response (pCR)	Pathological Minimal Residual Disease (pMRD): pathological minimal residual disease (pMRD) is defined as residual tumour 5mm or less.	6 years
Pathological Minimal Residual Disease (pMRD)	Pathological minimal residual disease is defined as residual tumour 5 mm or less.	6 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain level assessment	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.	6 years
Generic Quality of Life (QoL)	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.	6 years
Quality of Life-Prostate Cancer Patients	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.	6 years

Collaborators and Investigators

• Sponsor: University of British Columbia
• Collaborators: University Health Network, Toronto; Janssen Inc.
• Investigators: Study Chair: Martin E Gleave, MD, University of British Columbia

Study record dates

Study Major Dates

• Study Start (Actual): September 21, 2021
• Primary Completion (Estimated): April 1, 2026
• Study Completion (Estimated): April 1, 2026

Study Registration Dates

• First Submitted: March 12, 2021
• First Submitted That Met QC Criteria: March 19, 2021
• First Posted (Actual): March 23, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 11, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Prostatic Neoplasms; Antineoplastic Agents, Immunological; Poly(ADP-ribose) Polymerase Inhibitors; Immune Checkpoint Inhibitors; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Enzyme Inhibitors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Steroid Synthesis Inhibitors; Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Docetaxel; Abiraterone Acetate; Atezolizumab; Prednisone; Niraparib
• Other Study ID Numbers: H20-03434

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes