Inclusion
1. Histologically confirmed adenocarcinoma of the prostate
2. Greater than or equal to 18 years of age
3. ECOG performance status 0-1
4. PSA progression while on darolutamide defined as three rising PSA (1 baseline and 2 consecutive rises) levels at least 1 week apart despite castrate testosterone level (less than 1.7nmol/L). Patients with a minor subsequent PSA fall in the second or third value, provided there was no intervening therapy since the three consecutive rises, are eligible.
5. AJCC stage M0 on conventional imaging
a. Previous PSMA PET only M1 disease in the hormone-sensitive setting that is now M0 CRPC on conventional imaging following more than 18 months of ADT + darolutamide are eligible.
b. Nodes up to 2cm in short-axis in pelvis are permitted
6. PSA level more than 1.0 ng/mL during screening
7. Serum testosterone level less than 1.7nmol/L and on an LHRH agonist/antagonist
8. Adequate bone marrow function (platelets level more than 100 x 109/L, ANC more than 1.5 x 109/L, Hb more than 90)
9. Adequate liver function (ALT or AST less than 2.5 x ULN, bilirubin less than 1.5 x ULN)
10. Adequate renal function (creatinine less than 1.5 x ULN)
11. Willingness and ability to comply with study requirements, including treatment and timing of treatment.
Exclusion
1. Life expectancy less than 3 months.
2. Neuroendocrine or small cell prostate cancer on any prior diagnostic tissue sample.
3. Metastatic prostate cancer on conventional imaging (WBBS or CT scan) at any point in disease course (except for pathological nodes up to 2cm in short-axis in the pelvis)
4. Current or prior treatment with enzalutamide, abiraterone, apalutamide, or cytotoxic chemotherapy. Patients with pelvic nodal metastases (below the aortic bifurcation) less than 2cm in short axis at original diagnosis who ceased cytotoxic chemotherapy (docetaxel) at least 12 months prior to C1D1 are eligible. Prior first generation ARSI such as bicalutamide, flutamide, nilutamide are permitted.
5. Current or pre-existing cardiac or thromboembolic risk factors, including but not limited to:
i. Prior myocardial infarction, or unstable angina within 24 months of study entry,
ii. Uncontrolled or symptomatic cardiac disease including, but not limited to angina, dyspnoea on exertion, orthopnoea; cardiac failure (NYHA classification 3-4) or uncontrolled arrhythmias.
iii. Significant co-morbidities that increase cardiovascular risk, including significant hypertension (Baseline systolic BP more than 160 or diastolic BP more than 100 despite optimal treatment) that are uncontrolled, as assessed by the treating oncologist.
6. Another malignancy diagnosis within 2 years before registration. Participants with a history of treated carcinoma in situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or non-muscle invasive urothelial carcinoma of the bladder are eligible if malignancy has been treated with curative intent. Participants with a history of other malignancies are eligible if they have been continuously disease-free for at least 2 years after definitive primary treatment or the chance of recurrence is sufficiently low as to be very unlikely to affect study outcomes according to the treating local oncologist.
7. Concurrent illness that could preclude the participant’s ability to participate in the study and follow protocol with reasonable safety.
8. Planned ongoing drug Interactions as per section 5.2.4 that are considered unable to be managed prior to study registration.
9. Radiation therapy within the previous 4 weeks (participants are permitted to have SBRT to PSMA PET only disease prior to study enrolment if they continue on darolutamide. Note that if the metastases are visible on conventional imaging at the time of radiation treatment the participant is not eligible).