Clinical Trials

Inclusion Criteria: 

• Capable of giving signed informed consent as described in Appendix 1 (Section 10.1.3), which includes compliance with the requirements, restrictions listed in the informed consent form (ICF), and in this protocol.
• Male ≥ 18 years of age at the time of signing the informed consent.
• Histologically or cytologically confirmed adenocarcinoma of prostate.
• Prostate cancer initially treated by radical prostatectomy (RP) followed by adjuvant radiotherapy (ART) or salvage radiotherapy (SRT), or unfit for radiotherapy (RT) or initially treated by primary RT.
• High-risk biochemical recurrence (BCR), defined as
  • Prostate-specific antigen doubling time (PSADT) < 12 months, AND;
  • For PSMA PET/CT negative patients:
    • PSA ≥ 0.5 ng/mL after ART or SRT post RP or unfit for radiation or;
    • PSA ≥ 2 ng/mL above the nadir after primary RT only.
  • For PSMA PET-CT positive patients
    • PSA ≥ 0.2 ng/mL after ART or SRT post RP or unfit for radiation or;
    • PSA ≥ 2 ng/mL above the nadir after primary RT only.
• Participants must undergo prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) within the 30 days screening period using either 18F-DCFPyL (piflufolastat F18) or 68Ga-PSMA 11 which will be assessed by BICR.
• Serum testosterone ≥150 ng/dL (5.2 nmol/L).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Blood counts at screening:
  • Hemoglobin ≥ 9.0 g/dL (participant must not have received blood transfusion within 7 days prior to sample being taken);
  • Absolute neutrophil count (ANC) ≥1.5 x 10^9 /L (participant must not have received any growth factor within 4 weeks prior to sample being taken);
  • Platelet count ≥ 100 x 10^9 /L
• Screening values of:
  • Alanine aminotransferase (ALT) ≤ 1.5 x upper limit of normal (ULN);
  • Aspartate transaminase (AST) ≤ 1.5 x ULN;
  •  Total bilirubin ≤ 1.5 ULN, (except patients with a diagnosis of Gilbert’s disease);
  • Estimated glomerular filtration rate (eGFR) > 40 ml/min/1.73 m^2.
• Sexually active male participants must agree to use contraception as detailed in Section 10.4 (Appendix 4) of this protocol during the treatment period and for at least 3 months after the last dose of study treatment, and refrain from donating sperm during this period.

Exclusion Criteria:

• Pathological finding consistent with small cell, ductal or ≥ 50 % component of neuroendocrine carcinoma of the prostate.
• History of bilateral orchiectomy.
• Metastases or recurrent /new malignant lesions in prostate gland/bed seminal vesicles, lymph nodes below the CIA bifurcation on conventional imaging (CI) as assessed by BICR.
• Brain metastasis on PSMA PET /CT by BICR at screening.
• High-risk BCR after primary radiotherapy with new loco-regional lesions on screening PSMA PET/CT who are eligible for curative salvage prostatectomy;
  • Note: Patients treated with curative salvage prostatectomy after primary RT who meet the PSA criteria (inclusion criteria 5) may be considered for the study.
• Prior treatment with second generation (e.g. enzalutamide, apalutamide) androgen receptor inhibitors (ARIs) and CYP 17 inhibitors (e.g., abiraterone) within 18 months prior to signing of the ICF.
• Prior treatments with PSMA-radiotherapeutics within 12 months prior randomization.
• Prior image-guided radiotherapy as primary, adjuvant or salvage treatment completed within 8 weeks prior to signing of the ICF.
• Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs.
• Contraindication to PSMA PET/CT tracer, or both CT and MRI contrast agents (Section 8.1.2).
• Any prior malignancy (other than adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, or any other cancer in situ currently in complete remission) within 5 years.
• History of pelvic radiotherapy for other malignancy.
• Ongoing or active infection (bacterial, fungal, or viral including Hepatitis viral and Hepatitis B reactivation) requiring systemic therapy.
• Any positive test result for Hepatitis B virus (HBV) or Hepatitis C virus (HCV) indicating the presence of virus:
  • Active HBV (chronic or acute; defined as having a known positive Hepatitis B surface antigen [HBsAg] test at the time of screening) except for participants on antiviral therapy for HBV with an undetectable or low viral load;
  • Participants with past HBV infection or resolved HBV infection (defined as the presence of Hepatitis B core antibody [HBcAb] and absence of HBsAg) are eligible if HBV DNA is negative;
  • Participants positive for HCV antibody unless polymerase chain reaction is negative for HCV RNA;
  • Note: Hepatitis B and C testing is not required unless mandated by local authority.
• Known human immunodeficiency virus (HIV) infection with any of the following:
  • CD4+ T-cell (CD4+) count of less than 350 cells/µL
  • History of AIDS defining opportunistic infection within the past 12 months;
  • On established antiretroviral therapy for less than 4 weeks;
  • Presenting with a viral load of more than 400 copies/mL prior to enrollment;
  • On antiretroviral therapy or prophylactic antimicrobials that are expected to cause significant drug-drug interactions or overlapping toxicities with study treatment and cannot be changed to alternative agents;
  • Note: HIV testing is not required unless mandated by local authority.
• Had any of the following within 6 months before randomization: stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, congestive heart failure (New York Heart Association Class III or IV).
• Hypertension as indicated by a resting systolic blood pressure (BP) > 140 mmHg or diastolic BP ≥ 100 mmHg despite medical management.
• A gastrointestinal disorder or procedure which is expected to interfere significantly with absorption of study drug.
• Previous (within 28 days before the start of darolutamide/placebo or 5 half-lives of the investigational treatment of the previous study, whichever is longer) or concomitant participation in another clinical study with investigational medicinal product(s).
• Any other serious or unstable illness, or medical, social, or psychological condition, that could jeopardize the safety of the participant and/or his/her compliance with study procedures or may interfere with the participant’s participation in the study or evaluation of the study results.
• Inability to swallow oral medications.

Eligibility last updated 6/21/22. Questions regarding updates should be directed to the study team contact.