Working Out M0 Bipolar Androgen Therapy

Inclusion Criteria:

1. Histologically confirmed adenocarcinoma of the prostate

2. ≥18 years of age

3. ECOG performance status 0-1

4. PSA progression while on darolutamide defined as three rising PSA (1 baseline and 2consecutive rises) levels at least 1 week apart despite castrate testosterone level (<1.7nmol/L).

5. AJCC stage M0 on conventional imaging.

6. Previous PSMA PET only M1 disease in the hormone-sensitive setting that is nowM0 CRPC on conventional imaging following >18 months of ADT + darolutamide areeligible.

7. Nodes up to 2cm in short-axis in pelvis are permitted

8. PSA >1.0 ng/mL during screening

9. Serum testosterone <1.7nmol/L and on an LHRH agonist/antagonist

10. Adequate bone marrow function (platelets > 100 x 109/L, ANC > 1.5 x 109/L, Hb >90)

11. Adequate liver function (ALT or AST < 2.5 x ULN, bilirubin < 1.5 x ULN)

12. Adequate renal function (creatinine <1.5 x ULN)

13. Willingness and ability to comply with study requirements, including treatment andtiming of treatment.

Exclusion Criteria:

1. Life expectancy <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 indisease course (except for pathological nodes up to 2cm in short axis in thepelvis).

4. Current or prior treatment with enzalutamide, abiraterone, apalutamide, or cytotoxicchemotherapy. Prior first generation ARSI such as bicalutamide, flutamide,nilutamide are permitted.

5. Current or pre-existing cardiac or thromboembolic risk factors, including but notlimited to: i. Prior myocardial infarction, or unstable angina within 24 months of study entry,ii. Uncontrolled or symptomatic cardiac disease including, but not limited toangina, dyspnoea on exertion, orthopnoea; cardiac failure (NYHA classification 3-4)or uncontrolled arrhythmias. iii. Significant co-morbidities that increase cardiovascular risk, includingsignificant hypertension (Baseline systolic BP>160 or diastolic BP>100 despiteoptimal treatment) that are uncontrolled, as assessed by the treating oncologist.

6. Another malignancy diagnosis within 2 years before registration. Participants with ahistory of treated carcinoma in situ, basal cell carcinoma of the skin, squamouscell carcinoma of the skin, or non-muscle invasive urothelial carcinoma of thebladder are eligible if malignancy has been treated with curative intent.Participants with a history of other malignancies are eligible if they have beencontinuously disease-free for at least 2 years after definitive primary treatment orthe chance of recurrence is sufficiently low as to be very unlikely to affect studyoutcomes according to the treating local oncologist.

7. Concurrent illness that could preclude the participant's ability to participate inthe study and follow protocol with reasonable safety.

8. Planned ongoing drug Interactions as per protocol section 5.2.4 that are consideredunable to be managed prior to study registration.

9. Radiation therapy within the previous 4 weeks (participants are permitted to haveSBRT to PSMA PET only disease prior to study enrolment if they continue ondarolutamide. Note that if the metastases are visible on conventional imaging at thetime of radiation treatment the participant is not eligible).