Clinical trial NCT06594926: Working Out M0 Bipolar Androgen Therapy
Official title: Evaluating the Efficacy of Bipolar Androgen Therapy in Extending Metastasis-free Survival in Patients With M0 Castrate-resistant Prostate Cancer With PSA Progression But Not Radiological or Clinical Progression on Darolutamide
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Prostate Cancer
Keywords: darolutamide
testosterone
bipolar androgen therapy
Lead sponsor: Australian and New Zealand Urogenital and Prostate Cancer Trials Group
Sponsor class: OTHER
Collaborators: name: Bayer
name: The George Institute
name: HMRI
First posted: 2024-09-19
Enrollment: 69
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This is a single-arm phase 2 prospective, interventional study to assess the efficacy and safety of cyclical testosterone and darolutamide in non-metastatic castration-resistant prostate cancer.
Primary purpose: TREATMENT

Brief summary: 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)

Detailed description: 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).

Primary outcomes:
measure: Metastases free survival
timeFrame: From date of commencing Bipolar Androgen Therapy (BAT) until first documented evidence of metastatic disease or date of death, assessed every 8 weeks, on average 4 years
Secondary outcomes:
measure: Safety and tolerability of BAT + darolutamide
timeFrame: Continuously throughout the study, from time of commencing BAT until 30 days after last dose of treatment
measure: The effect of BAT + darolutamide on Health-related Quality of Life QLQ-C30
timeFrame: During screening and then every 2 weeks upon commencement of BAT for 8 weeks and then every 4 weeks until last dose of treatment, on average 2 years.
measure: The effect of BAT + darolutamide on Health-related Quality of Life QLQ-PR25
timeFrame: During screening and then every 2 weeks upon commencement of BAT for 8 weeks and then every 4 weeks until last dose of treatment, on average 2 years.
measure: PSA response rate to BAT + darolutamide
timeFrame: During screening and then every 2 weeks from the time of commencing BAT for first 8 weeks and then every 4 weeks until last dose of treatment, on average 2 years
measure: Time to PSA progression on BAT + darolutamide
timeFrame: During screening and then every 2 weeks from the time of commencing BAT for first 8 weeks and then every 4 weeks until last dose of treatment, on average 2 years
measure: PSA and hormone kinetics in response to BAT + darolutamide. This will be assessed as a composite outcome.
timeFrame: Every 2 weeks for first 24 weeks from the time of commencing BAT
measure: The effect of BAT + darolutamide on metabolic and bone turnover markers and bone mineral density. This will be assessed as a composite outcome.
timeFrame: Serum/plasma/urine - at screening and at 6 and 12 months on treatment. Bone densitometry imaging - at screening and 12 months on treatment.
Other outcomes:
Locations:
city: Albury
country: Australia
facility: The Border Cancer Hospital
state: New South Wales
city: Darlinghurst
country: Australia
facility: St Vincents Hospital
state: New South Wales
city: St Leonards
country: Australia
facility: GenesisCare North Shore
state: New South Wales
city: Wahroonga
country: Australia
facility: Sydney Adventist Hospital
state: New South Wales
city: Chermside
country: Australia
facility: ICON Cancer Centre
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Ballarat
country: Australia
facility: Grampians Health
state: Victoria
city: Box Hill
country: Australia
facility: Eastern Health - Box Hill
state: Victoria
city: Malvern
country: Australia
facility: Cabrini Health
state: Victoria
Study officials:
affiliation: St Vincent's Hospital, Sydney
name: Anthony Joshua
role: STUDY_CHAIR
References: