Treatment for high-risk prostate cancer using advanced diagnostic techniques

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

This study is testing whether adding a new drug called darolutamide to standard radiation therapy can help men with high-risk prostate cancer do better than those who only get a placebo.

Quick facts

• Phase: Phase2; Phase3
• Study type: Interventional
• Enrollment: 493 (estimated)
• Ages: 18 Years and up
• Sex: Male
• Sponsor: Cancer Research Antwerp (Academic / other)
• Drugs / interventions: radiation
• Locations: 9 sites (Wilrijk, Antwerp and 8 other locations)
• Trial ID: NCT06282588 on ClinicalTrials.gov

What this trial studies

This clinical trial aims to improve outcomes for patients with high-risk localized or locally advanced prostate cancer by utilizing novel diagnostic radio- and molecular tracers. The study includes a randomized Phase 3 treatment intensification component and a non-randomized Phase 2 treatment de-intensification component. Patients will be stratified based on PSMA PET/CT scan results and Decipher genomic classifier scores to guide treatment decisions. The trial will evaluate the effectiveness of darolutamide combined with standard radiation therapy compared to a placebo.

Who should consider this trial

Good fit: Ideal candidates are men diagnosed with high-risk localized or locally advanced prostate cancer who meet specific criteria related to PSA levels, T-stage, Gleason score, and performance status.

Not a fit: Patients with low-risk prostate cancer or those who do not meet the eligibility criteria for high-risk disease may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could lead to more personalized and effective treatment strategies for high-risk prostate cancer patients.

How similar studies have performed: Other studies utilizing advanced imaging and genomic classifiers have shown promise in improving treatment outcomes, suggesting this approach may be beneficial.

Eligibility criteria

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 \[\> 0.85\] Decipher score is confirmed) or the non-randomized Phase 2 study (if a low/ intermediate \[≤ 0.85\] 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 (≤ 0.85) 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 (\> 0.85) 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.

Where this trial is running

Wilrijk, Antwerp and 8 other locations

• ZAS Sint-Augustinus — Wilrijk, Antwerp, Belgium (Recruiting)
• Azorg — Aalst, Belgium (Recruiting)
• AZ Sint-Jan — Bruges, Belgium (Recruiting)
• Saint Luc — Brussels, Belgium (Recruiting)
• UZ Gent — Ghent, Belgium (Recruiting)
• AZ Groeninge — Kortrijk, Belgium (Recruiting)
• CHU Liège — Liège, Belgium (Recruiting)
• AZ Delta — Roeselare, Belgium (Recruiting)
• Vitaz — Sint-Niklaas, Belgium (Recruiting)

Study contacts

• Principal investigator: Piet Ost, MD,PhD — Gasthuis Zusters Antwerpen
• Study coordinator: Piet Ost, MD, PhD

Conditions Prostate Cancer; High-risk; PSMA PET/CT scan; Decipher