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

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 clinicalassessment acceptable for clinical T staging including physical exam (DRE),transrectal ultrasound, CT or MRI. Documentation for the N1 stage can be defined on CTor 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.
5. 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 describedin the study imaging manual), will be eligible to be randomized to either arm ofthe Phase 3 study. A lesion is considered positive if it has a E-PMSA score of 4or 5.
6. Pending confirmation of their Decipher score, subjects who are PSMA PET/CTnegative for regional or distant lesions at screening (PSMA PET scans will beassessed as described in the study imaging manual), will be eligible forinclusion in either the Phase 3 study (if a high [> 0.6] Decipher score isconfirmed) or the non-randomized Phase 2 study (if a low/ intermediate [≤ 0.6]Decipher score is confirmed).
7. Willingness to have their primary tumor sequenced for determination of Decipher score
8. Subjects who have a negative PSMA PET/ CT and a tumor with a low/ intermediateDecipher score (≤ 0.6) will be eligible to enter the non-randomized Phase 2study.
9. 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.
10. In subjects with positive PSMA PET/ CT, the Decipher score will not determine thetreatment allocation.
11. Willingness to undergo SOC RT and long-term ADT (treatment with darolutamide and/ orLHRHA)
12. Subject is able and willing to provide written informed consent, which includescompliance with and ability to undergo all study procedures and attend the scheduledfollow-up visit/s per protocol.
13. Subject must be over 18 years of age.
14. Subject able to swallow whole study drug tablets.
15. 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 monthsafter the last administration of study treatment. Donation of sperm is not allowedduring the treatment phase and for 3 months after the last administration of studytreatment.
16. Adequate organ function determined by the following local laboratory values:
17. Adequate bone marrow function: Hemoglobin ≥ 100 g/L, white cell count (WCC) ≥ 4.0x 109/L, absolute neutrophil count (ANC) ≥ 1.5 x 109/L and platelets > 100 x 109/L
18. Adequate renal function: calculated creatinine clearance > 30 mL/min (Cockroft-Gault)
19. Adequate liver function: ALT < 2 x upper limit of normal (ULN) and totalbilirubin < 1.5 x ULN, (or if total bilirubin is between 1.5 to 2 x ULN, theymust have a normal conjugated bilirubin)
20. 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 orneuroendocrine 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 focusedultrasound [HIFU], cryotherapy). Subjects with previous transurethral resection of theprostate (TURP) or Millin prostatectomy are eligible for participation
8. Prior systemic therapy for PCa, except for patients with a positive PSMA PET/ CTstaging 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 isstopped ≥ 2 weeks prior to enrollment, the subject is eligible.
10. Current chronic use of opioid analgesics, for ≥3 weeks for oral or ≥7 days fornon-oral formulations
11. History of seizure or any condition that may predispose to seizure (including, but notlimited to prior stroke, transient ischemic attack or loss of consciousness within ≤1year prior to enrollment; brain arteriovenous malformation; or intracranial massessuch as schwannomas and meningiomas that are causing edema or mass effect)
12. Any condition for which, in the opinion of the Investigator, participation would notbe in the best interest of the subject
13. Major surgery within 21 days prior to enrollment.
14. History of:
15. Loss of consciousness or transient ischemic attack or stroke within 6 monthsprior to enrollment, or
16. Significant cardiovascular disease within 6 months prior to enrollment: includingmyocardial infarction, unstable angina, congestive heart failure (New York HeartAssociation [NYHA] classification Grade 2 or greater), ongoing arrhythmias ofGrade > 2 (National Cancer Institute Common Terminology Criteria for AdverseEvents [NCI-CTCAE] v5.0), thromboembolic events (e.g., deep vein thrombosis,pulmonary embolism), coronary artery bypass graft. Chronic stable atrialfibrillation on stable anticoagulant therapy is allowed.
17. Known GI disease or GI procedure that could interfere with the oral absorption ortolerance of darolutamide, including difficulty swallowing tablets
18. History of another malignancy within 5 years prior to enrollment except for thosemalignancies treated with curative intent with a predicted risk of relapse of lessthan 10% including but not limited to non-melanoma carcinoma of the skin; oradequately 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 withinthe last 5 years are to be discussed with study team before enrollment. Melanomain-situ and other adequately treated in-situ neoplasms are not considered malignanciesfor the purposes of eligibility assessment
19. Concurrent illness, including severe infection that might jeopardize the ability ofthe subject to undergo the procedures outlined in this protocol with reasonable safety (human immunodeficiency virus [HIV] infection is not an exclusion criterion if it iscontrolled with anti-retroviral drugs that are unaffected by concomitant darolutamide)
20. Subjects who are sexually active with women of childbearing potential and notwilling/able to use medically acceptable and highly effective forms of contraceptionduring study treatment and for at least 3 months after the last administration ofstudy treatment. Contraception must include: Additional birth control with low failurerate (less than 1% per year) when used consistently and correctly, e.g., combined (estrogen and progestogen containing) hormonal contraception associated withinhibition of ovulation (oral, intravaginal, transdermal), progestogen only hormonalcontraception associated with inhibition of ovulation (oral, injectable, implantable),intrauterine device (IUD), intrauterine hormone releasing system (IUS), bilateraltubal occlusion, vasectomized partner, true sexual abstinence.