Treatment of High-Risk Prostate Cancer Guided by Novel Diagnostic Radio- and Molecular Tracers (THUNDER)

Treatment of High-Risk Prostate Cancer Guided by Novel Diagnostic Radio- and Molecular Tracers (THUNDER): A Two-part Phase 2/ 3 Trial

This Investigator-initiated, Treatment of High-Risk Prostate Cancer Guided by Novel Diagnostic Radio- and Molecular Tracers (THUNDER) study will be conducted in subjects with high-risk localized or locally advanced prostate cancer (PCa). The study contains both a randomized Phase 3 treatment intensification study, as well as a treatment de-intensification non-randomized Phase 2 study. The aim of the THUNDER study is to improve the outcome of high-risk PCa by improved risk stratification. Novel radiotracers and a genomic classifier (Decipher) will be used to guide treatment decisions, instead of standard imaging which is limited by lower sensitivity and specificity.

The hypothesis for the study is that treatment intensification based on a positive PSMA PET/ CT scan or Decipher high score (> 0.6) improves time to new metastases detected on PSMA PET/ CT in high-risk PCa. In patients who are PSMA PET/ CT negative with a low/ intermediate Decipher score (≤ 0.6), it is hypothesized that treatment de-intensification will improve patient quality of life while maintaining a good oncological outcome.

The study will be conducted at multiple centers across Europe. Participation in the study will comprise a screening period, where the screening assessments must be completed before subjects are enrolled and randomized (only for Phase 3 subjects). Eligible, consenting subjects will then undergo treatment according to their assigned study phase and treatment group, to occur over up to 96 weeks (24 months) with a post-treatment follow-up period to monitor safety and efficacy. The study will be closed when 96 events have been registered for the primary endpoint, which is expected to be at 7-8 years from the time of randomization of the first subject.

Study Overview

• Status: Recruiting
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: Darolutamide; Radiation: Radiotherapy; Drug: Zoladex 3.6Mg Implant; Drug: Zoladex LA; Drug: Decapeptyl sustained release 22.5 mg; Drug: Decapeptyl sustained release 11.25 mg; Drug: Depo-Eligard 45 mg; Drug: Depo-Eligard 22.5 mg; Drug: Depo-Eligard 7.5 mg; Drug: Firmagon 120 MG Injection; Drug: Firmagon 80 MG Injection; Drug: Docetaxel; Drug: Darolutamide matched placebo

Detailed Description

Approximately 360 evaluable patients determined to have high-risk localized or locally advanced PCa, with PSMA positive non-localized disease or a Decipher high score (> 0.6) will be enrolled to the Phase 3 trial. Subjects with PSMA positive non-localized disease for which a Decipher result cannot be obtained, will also be enrolled to the Phase 3 study.

All Phase 3 subjects will be randomly assigned in a 1:1 ratio to receive darolutamide plus Luteinizing hormone releasing hormone (ant)-agonists (LHRHA), or darolutamide matched placebo plus LHRHA, for up to 96 weeks (24 months). All Phase 3 subjects will also receive primary standard of care (SOC) radiation therapy (RT). Subjects in Phase 3 should be commenced on an LHRHA and darolutamide or placebo within 14 days after randomization (unless started earlier) plus SOC RT. Only patients with a PSMA PET-CT showing more than 5 M1 lesions are allowed to receive docetaxel in both arms of the Phase 3 trial. Docetaxel should be started within 4 weeks from randomization. Randomization of Phase 3 subjects will be stratified by 1 versus > 1 high-risk features, N1 versus M1 PSMA positive versus PSMA negative disease, Decipher low/ intermediate versus high versus unknown score and clinical trial site.

Approximately 133 evaluable patients determined to have localized PCa by PSMA PET/ CT (PSMA negative) with a low/ intermediate Decipher test score (≤ 0.6) will enter the non-randomized, Phase 2, single treatment arm, de-intensification study. Subjects with localized PCa by PSMA PET/ CT who return a high Decipher score (> 0.6) will be enrolled and randomized into the Phase 3 study. Subjects with localized PCa by PSMA PET/ CT for which a Decipher result cannot be obtained, will be deemed ineligible for study participation.

All Phase 2 study subjects will receive darolutamide for the study duration for up to 96 weeks (24 months) and primary SOC RT.

• Study Type: Interventional
• Enrollment (Estimated): 493
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Piet Ost, MD, PhD; Phone Number: 003234433759; Email: cancertrials@gza.be

Study Locations

• Belgium
  • Aalst, Belgium, 9300
    • Not yet recruiting
    • OLVZ Aalst
    • Contact: Samuel Br
    • Principal Investigator: Samuel Bral
  • Brugge, Belgium, 8000
    • Not yet recruiting
    • AZ Sint-Jan
    • Contact: Sabine Meersschout
    • Principal Investigator: Sabine Meersschout
  • Bruxelles, Belgium, 1200
    • Not yet recruiting
    • Saint Luc
    • Contact: Ad Vanderm
    • Principal Investigator: Ad Vandermeulen
  • Edegem, Belgium, 2600
    • Not yet recruiting
    • UZA
    • Contact: Karen Fransis
    • Principal Investigator: Karen Fran
  • Gent, Belgium, 9000
    • Not yet recruiting
    • UZ Gent
    • Contact: Valérie Fonteyne
    • Principal Investigator: Valérie Fonteyne
  • Gent, Belgium, 900
    • Not yet recruiting
    • AZ Sint-Lucas
    • Contact: Lien Van De Voorde
    • Principal Investigator: Lien Van De Voor
  • Kortrijk, Belgium, 8500
    • Not yet recruiting
    • AZ Groeninge
    • Contact: Nick Liefhooghe
    • Principal Investigator: Nick Liefhooghe
  • Liège, Belgium, 4000
    • Not yet recruiting
    • CHU Liege
    • Principal Investigator: Brieuc Sautois
    • Contact: Brieuc Suatois
  • Roeselare, Belgium, 8800
    • Not yet recruiting
    • AZ DELTA
    • Contact: Benedikt Engels
    • Principal Investigator: Benedikt Enge
  • Sint-Niklaas, Belgium, 9100
    • Not yet recruiting
    • Vitaz
    • Contact: Bart De Troyer
    • Principal Investigator: Bart De Troyer
  • Antwerp
    • Wilrijk, Antwerp, Belgium, 2610
      • Recruiting
      • GZA Sint-Augustinus
      • Contact: Piet Ost, MD, PhD; Email: cancertrials@gza.be
      • Principal Investigator: Piet Ost

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Histopathology-proven PCa

2. High-risk locally advanced disease is defined as any of the following factors: PSA > 20 ng/mL OR T-stage 3 or 4 OR Gleason score 8-10 OR cN1.

   Note: documentation of the clinical T-stage may be obtained from any clinical assessment acceptable for clinical T staging including physical exam (DRE), transrectal ultrasound, CT or MRI. Documentation for the N1 stage can be defined on CT or MRI.

3. An Eastern Cooperative Oncology Group (ECOG) Performance Status grade of 0 or 1.

4. Willingness to undergo a PSMA PET/ CT with or without contrast.

   1. Subjects who are PSMA PET/ CT positive for at least one regional or distant (extra-pelvic) lesion at screening (PSMA PET scans will be assessed as described in the study imaging manual), will be eligible to be randomized to either arm of the Phase 3 study. A lesion is considered positive if it has a E-PMSA score of 4 or 5.
   2. Pending confirmation of their Decipher score, subjects who are PSMA PET/ CTnegative for regional or distant lesions at screening (PSMA PET scans will be assessed as described in the study imaging manual), will be eligible for inclusion in either the Phase 3 study (if a high [> 0.6] Decipher score is confirmed) or the non-randomized Phase 2 study (if a low/ intermediate [≤ 0.6] Decipher score is confirmed).

5. Willingness to have their primary tumor sequenced for determination of Decipher score

   1. Subjects who have a negative PSMA PET/ CT and a tumor with a low/ intermediate Decipher score (≤ 0.6) will be eligible to enter the non-randomized Phase 2 study.
   2. Subjects who have a negative PSMA PET/ CT and a tumor with a high Decipher score (> 0.6) will be eligible to be randomized to either arm of the Phase 3 study.
   3. In subjects with positive PSMA PET/ CT, the Decipher score will not determine the treatment allocation.
6. Willingness to undergo SOC RT and long-term ADT (treatment with darolutamide and/ or LHRHA)
7. Subject is able and willing to provide written informed consent, which includes compliance with and ability to undergo all study procedures and attend the scheduled follow-up visit/s per protocol.
8. Subject must be over 18 years of age.
9. Subject able to swallow whole study drug tablets.
10. To avoid risk of drug exposure through the ejaculate (even men with vasectomies), subjects must use a condom during sexual activity while on study drug and for 3 months after the last administration of study treatment. Donation of sperm is not allowed during the treatment phase and for 3 months after the last administration of study treatment.

11. Adequate organ function determined by the following local laboratory values:

    1. Adequate bone marrow function: Hemoglobin ≥ 100 g/L, white cell count (WCC) ≥ 4.0 x 109/L, absolute neutrophil count (ANC) ≥ 1.5 x 109/L and platelets > 100 x 109/L
    2. Adequate renal function: calculated creatinine clearance > 30 mL/min (Cockroft-Gault)
    3. Adequate liver function: ALT < 2 x upper limit of normal (ULN) and total bilirubin < 1.5 x ULN, (or if total bilirubin is between 1.5 to 2 x ULN, they must have a normal conjugated bilirubin)
    4. Testosterone levels > 50 ng/dL

Exclusion Criteria:

1. Definitive radiologic evidence of metastatic disease outside of the pelvic nodes (M1a, M1b or M1c) on conventional imaging (i.e., bone scan, CT scan, MRI)
2. PCa with predominant non-adenocarcinoma features (sarcomatoid or spindle or neuroendocrine small cell or squamous cell components or other non-adenocarcinoma)
3. Prior pelvic radiotherapy
4. Contraindications for pelvic radiotherapy
5. Contraindications for ADT (treatment with darolutamide and/ or LHRHA)
6. Contraindications or known allergy to PSMA PET/ CT tracers.
7. Prior local therapy for PCa (e.g., radical prostatectomy, high-intensity focused ultrasound [HIFU], cryotherapy). Subjects with previous transurethral resection of the prostate (TURP) or Millin prostatectomy are eligible for participation
8. Prior systemic therapy for PCa, except for patients with a positive PSMA PET/ CT staging with ADT started no more than 4 weeks prior to randomization.
9. Current use of 5-alpha reductase inhibitor Note: if the alpha reductase inhibitor is stopped ≥ 2 weeks prior to enrollment, the subject is eligible.
10. Current chronic use of opioid analgesics, for ≥3 weeks for oral or ≥7 days for non-oral formulations
11. History of seizure or any condition that may predispose to seizure (including, but not limited to prior stroke, transient ischemic attack or loss of consciousness within ≤1 year prior to enrollment; brain arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas that are causing edema or mass effect)
12. Any condition for which, in the opinion of the Investigator, participation would not be in the best interest of the subject
13. Major surgery within 21 days prior to enrollment.

14. History of:

    1. Loss of consciousness or transient ischemic attack or stroke within 6 months prior to enrollment, or
    2. Significant cardiovascular disease within 6 months prior to enrollment: including myocardial infarction, unstable angina, congestive heart failure (New York Heart Association [NYHA] classification Grade 2 or greater), ongoing arrhythmias of Grade > 2 (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] v5.0), thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism), coronary artery bypass graft. Chronic stable atrial fibrillation on stable anticoagulant therapy is allowed.
15. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of darolutamide, including difficulty swallowing tablets
16. History of another malignancy within 5 years prior to enrollment except for those malignancies treated with curative intent with a predicted risk of relapse of less than 10% including but not limited to non-melanoma carcinoma of the skin; or adequately treated, non-muscle-invasive urothelial carcinoma of the bladder (i.e., Tis, Ta and low grade T1 tumors). All such cases with a history of malignancy within the last 5 years are to be discussed with study team before enrollment. Melanoma in-situ and other adequately treated in-situ neoplasms are not considered malignancies for the purposes of eligibility assessment
17. Concurrent illness, including severe infection that might jeopardize the ability of the subject to undergo the procedures outlined in this protocol with reasonable safety (human immunodeficiency virus [HIV] infection is not an exclusion criterion if it is controlled with anti-retroviral drugs that are unaffected by concomitant darolutamide)
18. Subjects who are sexually active with women of childbearing potential and not willing/able to use medically acceptable and highly effective forms of contraception during study treatment and for at least 3 months after the last administration of study treatment. Contraception must include: Additional birth control with low failure rate (less than 1% per year) when used consistently and correctly, e.g., combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device (IUD), intrauterine hormone releasing system (IUS), bilateral tubal occlusion, vasectomized partner, true sexual abstinence.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 2 Open Label; Darolutamide for up to 96 weeks (24 months) and primary SOC RT	Drug: Darolutamide; 2x300 mg tablets twice daily, for up to 96 weeks; Other Names: Nubeqa; BAY1841788; Radiation: Radiotherapy; Preferred regimens: 60 to 62 Gy delivered in 20 fractions of 3.0 to 3.1Gy per fraction; 36.25 Gy delivered in 5 fractions of 7.25 Gy per fraction, 2-3 fractions per week
Experimental: Phase 3 Blinded Experimental; Darolutamide + LHRHA for up to 96 weeks (24 months) and primary SOC RT	Drug: Darolutamide; 2x300 mg tablets twice daily, for up to 96 weeks; Other Names: Nubeqa; BAY1841788; Radiation: Radiotherapy; Preferred regimens: 60 to 62 Gy delivered in 20 fractions of 3.0 to 3.1Gy per fraction; 36.25 Gy delivered in 5 fractions of 7.25 Gy per fraction, 2-3 fractions per week; Drug: Zoladex 3.6Mg Implant; 3.6 mg, subcutaneous use; Other Names: Goserelin acetate 3.6 mg; Drug: Zoladex LA; 10.8 mg, subcutaneous use; Other Names: Goserelin acetate 10.8 mg; Drug: Decapeptyl sustained release 22.5 mg; 22.5 mg, intramusculair injection; Other Names: Triptorelin 11.25 mg; Drug: Decapeptyl sustained release 11.25 mg; 11.25 mg, intramusculair injection; Other Names: Triptorelin 11.25 mg; Drug: Depo-Eligard 45 mg; 45 mg, subcutaneous use; Other Names: Leuprorelin acetate 45 mg; Drug: Depo-Eligard 22.5 mg; 22.5 mg, subcutaneous use; Other Names: Leuprorelin acetate 22.5 mg; Drug: Depo-Eligard 7.5 mg; 7.5 mg, subcutaneous use; Other Names: Leuprorelin acetate 7.5 mg; Drug: Firmagon 120 MG Injection; 120 mg, subcutaneous use; Other Names: Degarelix 40 mg; Drug: Firmagon 80 MG Injection; 80 mg, subcutaneous use; Other Names: Degarelix 20 mg; Drug: Docetaxel; 75 mg per square m, IV infusion; Other Names: Taxotere
Placebo Comparator: Phase 3 Blinded Comparator; Darolutamide matched placebo + LHRHA for up to 96 weeks (24 months) and primary SOC RT	Radiation: Radiotherapy; Preferred regimens: 60 to 62 Gy delivered in 20 fractions of 3.0 to 3.1Gy per fraction; 36.25 Gy delivered in 5 fractions of 7.25 Gy per fraction, 2-3 fractions per week; Drug: Zoladex 3.6Mg Implant; 3.6 mg, subcutaneous use; Other Names: Goserelin acetate 3.6 mg; Drug: Zoladex LA; 10.8 mg, subcutaneous use; Other Names: Goserelin acetate 10.8 mg; Drug: Decapeptyl sustained release 22.5 mg; 22.5 mg, intramusculair injection; Other Names: Triptorelin 11.25 mg; Drug: Decapeptyl sustained release 11.25 mg; 11.25 mg, intramusculair injection; Other Names: Triptorelin 11.25 mg; Drug: Depo-Eligard 45 mg; 45 mg, subcutaneous use; Other Names: Leuprorelin acetate 45 mg; Drug: Depo-Eligard 22.5 mg; 22.5 mg, subcutaneous use; Other Names: Leuprorelin acetate 22.5 mg; Drug: Depo-Eligard 7.5 mg; 7.5 mg, subcutaneous use; Other Names: Leuprorelin acetate 7.5 mg; Drug: Firmagon 120 MG Injection; 120 mg, subcutaneous use; Other Names: Degarelix 40 mg; Drug: Firmagon 80 MG Injection; 80 mg, subcutaneous use; Other Names: Degarelix 20 mg; Drug: Docetaxel; 75 mg per square m, IV infusion; Other Names: Taxotere; Drug: Darolutamide matched placebo; 2x300 mg tablets twice daily, for up to 96 weeks; Other Names: BAY1841788 matched placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 3: PSMA PET metastasis free survival (ppMFS)	Improvement in PSMA PET metastasis free survival (ppMFS)	Time from randomization to the date of at least 1 new PSMA-PET positive distant lesion as compared to baseline or date of death from any cause, assessed up to 42 months
Phase 2: quality of life (sexual subdomain)	EPIC mean changes in sexual subdomain scores over time will be compared, both for change from baseline and absolute scores	At 12 months
Phase 2: quality of life (hormonal subdomain)	EPIC mean changes in hormonal subdomain scores over time will be compared, both for change from baseline and absolute scores	At 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Overall survival	Time interval between randomization and time of death, assessed up to 42 months
Prostate-cancer specific survival	Prostate-cancer specific survival	Time interval between randomization and prostate cancer death, assessed up to 42 months
Biochemical progression-free survival	Increase in PSA of >2 ng/ml above the nadir PSA level	Measured from the date of randomization to the date event, or death or censored at the last known follow-up date, assessed up to 42 months
Time to next systemic therapy	Time to next systemic therapy	Measured from date of randomization to time of death, or censored at the last known follow-up date, assessed up to 42 months
Frequency and severity of adverse events	Frequency and severity of adverse events	From signing ICF until 30 days after the last dose of study treatment.

Collaborators and Investigators

• Sponsor: Cancer Research Antwerp
• Collaborators: Bayer; Veracyte, Inc.
• Investigators: Principal Investigator: Piet Ost, MD,PhD, Gasthuis Zusters Antwerpen

Study record dates

Study Major Dates

• Study Start (Actual): December 13, 2023
• Primary Completion (Estimated): July 31, 2030
• Study Completion (Estimated): December 31, 2030

Study Registration Dates

• First Submitted: January 19, 2024
• First Submitted That Met QC Criteria: February 26, 2024
• First Posted (Actual): February 28, 2024

Study Record Updates

• Last Update Posted (Actual): February 28, 2024
• Last Update Submitted That Met QC Criteria: February 26, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: High-risk; Decipher; PSMA PET/CT scan
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Hormonal; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptive Agents, Female; Fertility Agents, Female; Fertility Agents; Luteolytic Agents; Docetaxel; Leuprolide; Goserelin; Triptorelin Pamoate
• Other Study ID Numbers: CTO21042GZA

Drug and device information, study documents

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