WOMBAT / ANZUP 2201

1) Histologically confirmed adenocarcinoma of the prostate.

2) >=18 years of age.

3) Eastern Cooperative Oncology Group (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 (<1.7nmol/L).

5) PSA >2 ng/mL during screening.

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

7) Adequate bone marrow function.

8) Adequate liver function.

9) Adequate renal function.

10) Willingness and ability to comply with study requirements, including treatment and timing of treatment.

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 (Whole body bone scan (WBBS) or CT scan). Metastatic prostate cancer evident only on Prostate Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) (without correlation on CT and bone scan or on the CT component of a PET/CT) is not an exclusion.

4) Current or prior treatment with enzalutamide, abiraterone, apalutamide, or cytotoxic chemotherapy. Ketoconazole and cyproterone are also excluded. Prior first generation Androgen receptor signalling inhibitor (ARSI) such as bicalutamide, flutamide, nilutamide are permitted.

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

6) Another malignancy diagnosis within 5 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. Participants with a history of other malignancies are eligible if they have been continuously disease-free for at least 5 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 that are considered unable to be managed prior to study registration.

9) Radiation therapy within the previous 4 weeks (participants are permitted to have Stereotactic body radiotherapy (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).

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