Working Out M0 Bipolar Androgen Therapy

The WOMBAT study will test if BAT can prolong the time it takes for nmCRPC prostate cancer to become detectable in other areas of the body (metastatic disease).

Approximately 69 participants over the age of 18 with castrate resistant prostate cancer, no evidence of metastatic disease (M0) on conventional imaging (WBBS and CT scan at screening) and PSA only progression on darolutamide will be enrolled from approximately 8 sites within Australia.

Participants will receive continuous androgen deprivation therapy with LHRH agonists/antagonists. The study intervention will be IM testosterone enthanate, injected on day 1 of each 56-day cycle. Concurrent darolutamide will be taken at a dose of 600mg BD on days 29-56 of each cycle. Both LHRH and agonist/antagonist and darolutamide are supplied through the PBS as standard of care medications. Administration of both testosterone and darolutamide will continue until disease progression, beyond disease progression, unacceptable toxicity, death, withdrawal of consent or study Sponsor termination of the study.

Primary objective (endpoint) is to determine the metastasis-free survival (time from commencing BAT to evidence of metastases or death)

This is a study to assess the efficacy and safety of cyclical testosterone and darolutamide in non-metastatic castration-resistant prostate cancer.

Adults with castrate resistant prostate cancer, with no evidence of metastatic disease (M0) on conventional imaging \[Whole Body Bone Scan (WBBS) and Computed Tomography (CT) scan at screening\] and prostate specific antigen (PSA) only progression on darolutamide may be eligible.

Study participants will receive cyclical treatment with intramuscular (IM) testosterone, darolutamide and ongoing medical/surgical castration. This will be delivered in 56-day cycles until evidence of metastatic disease on conventional imaging unless treated beyond progression. Participants will be asked to provide blood samples, complete questionnaires and undergo scans during their treatment.

It is hoped that findings from this study will help develop new treatment pathways for those with non-metastatic castration-resistant prostate cancer.

Eligibility Criteria:
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 2 consecutive rises) levels at least 1 week apart despite castrate testosterone level (\<1.7nmol/L).
5. AJCC stage M0 on conventional imaging.

   1. Previous PSMA PET only M1 disease in the hormone-sensitive setting that is now M0 CRPC on conventional imaging following \>18 months of ADT + darolutamide are eligible.
   2. Nodes up to 2cm in short-axis in pelvis are permitted
6. PSA \>1.0 ng/mL during screening
7. Serum testosterone \<1.7nmol/L and on an LHRH agonist/antagonist
8. Adequate bone marrow function (platelets \> 100 x 109/L, ANC \> 1.5 x 109/L, Hb \>90)
9. Adequate liver function (ALT or AST \< 2.5 x ULN, bilirubin \< 1.5 x ULN)
10. Adequate renal function (creatinine \<1.5 x ULN)
11. Willingness and ability to comply with study requirements, including treatment and timing 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 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. 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\>160 or diastolic BP\>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 protocol 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).