Darolutamide + Consolidation Radiotherapy in Advanced Prostate Cancer Detected by PSMA (DECREASE)

Inclusion Criteria:

• Males aged 18 years or older.
• Has provided written Informed Consent for participation in this trial.
• Histological or cytologically confirmed adenocarcinoma of prostate without neuroendocrine differentiation or small cell features.
• Castration-resistant prostate cancer (CRPC) defined as at least 2 consecutive PSA rises obtained at least 1 week apart in the setting of castrate testosterone levels (see below). If the patient has a history of anti-androgen use and recent withdrawal, the most recent PSA value must be obtained at least 4 weeks after anti-androgen withdrawal.
• Castrate level of serum testosterone (<1.7 nmol/l [50 ng/dl]) on gonadotrophin - releasing hormone (GnRH) agonist or antagonist therapy or after bilateral orchiectomy. Patients who have not undergone bilateral orchiectomy must continue GnRH therapy during the study.
• A baseline PSA level of at least 2ng per millilitre and a PSA doubling time of 10 months or less.
• An ECOG performance status score of 0 or 1.
• Blood counts at screening: haemoglobin ≥9.0 g/dl, absolute neutrophil count ≥1500/μl (1.5×109/l), platelet count ≥100,000/μl (100×109/l) (patient must not have received any growth factor or blood transfusion within 7 days of the haematology laboratory obtained at screening).
• Screening values of serum alanine transaminase (ALT) and aspartate transaminase (AST) ≤2.5 x upper limit of normal (ULN), total bilirubin ≤1.5 x ULN (except patients with a diagnosis of Gilbert's disease), creatinine ≤2.0 x ULN.

• At least 1 site of PSMA-avid disease on PSMA-PET imaging in any of the following regions:

  • Local recurrence within the prostate gland or prostate bed
  • Regional lymph node disease (below the aortic bifurcation)
  • Extra-pelvic lymph node, bone or soft tissue metastatic disease

Exclusion Criteria:

• Patients with detectable metastases or a history of metastatic disease on conventional imaging (whole body bone scan and computed tomography (CT) of the pelvis, abdomen and chest). NOTE: Presence of pelvic lymph nodes <2 cm in short axis below the aortic bifurcation is allowed.
• Prior treatment with: (1) second-generation androgen receptor (AR) antagonists such as enzalutamide and apalutamide, or darolutamide or other investigational AR antagonists; (2) CYP17 enzyme inhibitors, such as abiraterone acetate and orteronel; or (3) oral ketoconazole.
• Use of estrogens or 5-α reductase inhibitors (finasteride, dutasteride) or anti-androgens (bicalutamide, flutamide, nilutamide, cyproterone acetate) within 28 days before randomisation.
• Use of systemic corticosteroid with a dose greater than the equivalent 10 mg of prednisone/day within 28 days before randomisation.
• Radiation therapy (external beam radiation therapy [EBRT], brachytherapy, or radiopharmaceuticals) within 12 weeks prior to randomisation.
• Initiation of treatment with an osteoclast-targeted therapy (bisphosphonate or denosumab) to prevent skeletal-related events within 12 weeks before randomisation. NOTE: Patients receiving osteoclast-targeted therapy to prevent bone loss at a dose and schedule indicated for osteoporosis may continue treatment at the same dose and schedule, providing it was commenced at least 28 days before randomisation.
• Any of the following within 6 months before randomisation: stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft; congestive heart failure New York Heart Association (NYHA) Class III or IV.
• Uncontrolled hypertension as indicated by a systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg at screening.
• Prior malignancy. NOTE: Adequately treated basal cell or squamous cell carcinoma of skin or superficial bladder cancer that has not spread behind the connective tissue layer (i.e., pTis, pTa, and pT1) is allowed, as well as any other cancer for which the last anti-cancer therapeutic intervention has been completed - 5 years ago and from which the patient has been disease-free.
• Gastrointestinal disorder or procedure that expects to interfere significantly with the absorption of study treatment.
• Unable to swallow study medications and comply with study requirements.