Darolutamide and bipolar androgen therapy for mCRPC patients (DaroBAT)

Prior treatment

• Major surgery (e.g., requiring general anesthesia) within 4 weeks before screening, or patients not fully recovered from prior surgery (i.e., unhealed wound). Note: subjects with planned surgical procedures to be conducted under local anesthesia may participate
• Current participation in any other clinical trial or use of any other IMP within the last 30 days prior to screening visit or within 5 half-lives of the IMP (whichever is longer) and throughout the trial
• Prior systemic treatment for mCRPC
• 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)
• Prior history of a thromboembolic event within the last 12 months that is not being treated with systemic anticoagulation

Other illness

• Pain due to metastatic prostate cancer > NRS 3 and/or requiring the onset or escalation of opioid treatment. Note: Patients should be on a stable dose for at least four weeks.
• Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs
• History of seizures
• Hepatic metastases and/or evidence of disease in sites or extent that, in the opinion of the investigator, would put the patient at risk from therapy with testosterone (e.g., femoral metastases with concern over fracture risk, severe and extensive spinal metastases with concern over spinal cord compression, progression on first line antihormonal therapy within 6 months)
• Active uncontrolled infection, including known history of HIV/AIDS or hepatitis B or C
• Any psychological, familial, sociological, or geographical condition that could potentially interfere with compliance with the study protocol and follow-up schedule
• Uncontrolled hypertension as indicated by a resting systolic blood pressure (BP) ≥ 160 mmHg or diastolic BP ≥ 100 mmHg despite medical treatment

Lab values

• Long QT-syndrome
• Evidence of serious and/or unstable pre-existing medical, psychiatric or other condition (including laboratory abnormalities) that could interfere with patient safety or provision of informed consent to participate in this study

Age

• Prior malignancy, except prostate cancer, adequately treated basal cell or squamous cell carcinoma of skin or superficial bladder cancer or cancer for which treatment has been completed ≥ 5 years before randomization and from which the participant has been disease-free

Other

• Known BRCA-mutations
• Thrombophilia
• Migraine
• Active brain metastases. Note: Subjects with treated, asymptomatic and clinically stable metastases are eligible.
• Any dependent relationship of the subject with the investigator, trial site or sponsor/sponsor’s delegate (e.g., employees or relatives)
• Institutionalization because of legal or regulatory order

• Ability to understand and willingness to sign a written informed consent form (ICF) document
• Acceptable liver function: •Bilirubin ≤ institutional upper limit of normal (ULN) •aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) < 1.5 times ULN
• Acceptable renal function: •Serum creatinine < 2.0 times ULN
• Acceptable hematologic status: •Absolute neutrophil count (ANC) ≥ 1500 cells/mm3 (1.5 ×109/L) •Platelet count ≥ 100,000 platelet/mm3 (100 ×109/L) •Hemoglobin ≥ 9 g/dL
• At least 4 weeks since prior radiation
• Sexually active male subjects must agree to use condoms as an effective barrier method and refrain from sperm donation, and their female partners of child-bearing potential to use a method of highly effective birth control during treatment and for 6 months thereafter
• Eastern Cooperative Oncology Group Performance status (ECOG PS) grade ≤2
• Men ≥18 years
• Histologically-confirmed adenocarcinoma of the prostate
• Treatment with continuous androgen ablative therapy (either surgical castration or luteinizing hormone-releasing hormone (LHRH)-agonist/antagonist) in combination with an ARI (Apalutamide, Darolutamide, or Enzalutamide, as currently approved for mCSPC)
• Documented castrate level of serum testosterone (<50 ng/dl)
• Metastatic disease radiographically documented by CT/MRI, bone scan or PSMA-PET-CT
• Disease progression while on Apalutamide, Darolutamide or Enzalutamide as currently approved based on: PSA progression defined as an over 25% increase in PSA, as determined within two consecutive measurements separated by at least one week and/or Radiographic disease progression, based on RECIST 1.1 in patients with measurable soft tissue lesions, or PCWG3 for patients with bone disease
• Screening PSA ≥ 1.0 ng/mL