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 (\> 0.85) 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 (≤ 0.85), 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.
• Histopathology-proven PCa
• 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.
• An Eastern Cooperative Oncology Group (ECOG) Performance Status grade of 0 or 1.
• Willingness to undergo a PSMA PET/ CT with or without contrast.
∙ 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.
‣ 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).
• Willingness to have their primary tumor sequenced for determination of Decipher score
∙ 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.
‣ 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.
‣ In subjects with positive PSMA PET/ CT, the Decipher score will not determine the treatment allocation.
• Willingness to undergo SOC RT and long-term ADT (treatment with darolutamide and/ or LHRHA)
• 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.
• Subject must be over 18 years of age.
• Subject able to swallow whole study drug tablets.
⁃ 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.
⁃ Adequate organ function determined by the following local laboratory values:
• 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
∙ Adequate renal function: calculated creatinine clearance \> 30 mL/min (Cockroft-Gault)
∙ 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)
∙ Testosterone levels \> 50 ng/dL