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Working Out M0 Bipolar Androgen Therapy

PHASE2RECRUITING

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).

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Study details:

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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

Histologically confirmed adenocarcinoma of the prostate

≥18 years of age

ECOG performance status 0-1

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).

PSA >2 ng/mL during screening

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

Adequate bone marrow function (platelets > 100 x 10^9/L, ANC > 1.5 x 10^9/L, Hb >90)

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

Adequate renal function (creatinine <1.5 x ULN)

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

Exclusion criteria

Life expectancy <3 months.

Neuroendocrine or small cell prostate cancer on any prior diagnostic tissue sample.

Metastatic prostate cancer on conventional imaging (WBBS or CT scan). Metastatic prostate cancer evident only on PSMA PET (without correlation on CT and bone scan or on the CT component of a PET/CT) is not an exclusion.

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

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.

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.

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

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

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).

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Eligibility

Age eligible for study : 18 and older

Healthy volunteers accepted : No

Gender eligible for study: Male

Things to know

Study dates

Study start: 2024-08-14

Primary completion: 2026-12-31

Study completion finish: 2028-12-31

Study type

TREATMENT

Phase

PHASE2

Trial ID

NCT06594926

Intervention or treatment

DRUG: Testosterone Enanthate

Conditions

• Prostate Cancer

Condition: Prostate Cancer
DRUG: Testosterone Enanthate
St Leonards, New South Wales, Australia and more
Sponsor: Australian and New Zealand Urogenital and Prostate Cancer Trials Group

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Find a site

Closest Location:

GenesisCare North Shore

Research sites nearby

Select from list below to view details:

GenesisCare North Shore
St Leonards, New South Wales, Australia
Sydney Adventist Hospital
Wahroonga, New South Wales, Australia
Royal Adelaide Hospital
Adelaide, South Australia, Australia
St Vincents Hospital
Darlinghurst, New South Wales, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Testosterone enthanate 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 (+3 days) except for cycle 1. 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.	DRUG: Testosterone Enanthate Testosterone enanthate is a depot formulation used in Australia typically for androgen replacement in people with confirmed testosterone deficiency.

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Testosterone enthanate

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 (+3 days) except for cycle 1. 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.

DRUG: Testosterone Enanthate

Testosterone enanthate is a depot formulation used in Australia typically for androgen replacement in people with confirmed testosterone deficiency.

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
Metastases free survival	Based on PCWG3 criteria (appendix 2) and/or RECIST1.1 (appendix 1) on CT and WBBS imaging.	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 outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
Safety and tolerability of BAT + darolutamide	The safety and tolerability of BAT + darolutamide (Incidence and grade of AEs by NCI CTCAE v5.0 Common Terminology Criteria for Adverse Events will be used to grade and classify adverse events after each cycle. Adverse events will be reported as all grade, grade 3-4, grade 5 and Adverse events of special interest (related to bipolar androgen therapy).	Continuously throughout the study, from time of commencing BAT until 30 days after last dose of treatment
The effect of BAT + darolutamide on Health-related Quality of Life QLQ-C30	Using the European Organisation for Research Treatment of Cancer (EORTC) quality of life (QOL) questionnaire QLQ-C30. QLQ-C30 uses 28 questions about overall QOL with each question answerable using a scale from 1 (not at all) to 4 (very much). Overall scores can be from a minimum of 28 indicating a better QOL and higher scores with a maximum of 112 indicating lower overall QOL. It has two summary questions which asks participants to rank, 1) overall health and 2) overall QOL on scale from 1: very poor, to 7; excellent.	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.
The effect of BAT + darolutamide on Health-related Quality of Life QLQ-PR25	Using the European Organisation for Research Treatment of Cancer (EORTC) quality of life (QOL) questionnaire QLQ-PR25. QLQ-PR25 is a supplement to QLQ-C30 and designed to assess symptoms related to prostate cancer, treatment, and aspects of life related to prostate cancer.QLQ-PR25 uses 25 questions about overall QOL with each question answerable using a scale from 1 (not at all) to 4 (very much). Overall scores can be from a minimum of 25 indicating a better QOL and higher scores with a maximum of 100 indicating lower overall QOL.	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.
PSA response rate to BAT + darolutamide	By testing PSA level in blood. PSA response rate is defined as a PSA reduction of \>=50% from baseline as per PCWG3 criteria	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
Time to PSA progression on BAT + darolutamide	By testing PSA level in blood. PSA progression is defined as a PSA increase of \>=25% from baseline or nadir, confirmed on subsequent test \>=1 week later as per PCWG3)	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
PSA and hormone kinetics in response to BAT + darolutamide. This will be assessed as a composite outcome.	Blood tests assessing change in PSA, testosterone, oestradiol, Dihydrotestosterone (DHT), Dehydroepiandrosterone (DHEA), sex hormone-binding globulin (SBHG)	Every 2 weeks for first 24 weeks from the time of commencing BAT
The effect of BAT + darolutamide on metabolic and bone turnover markers and bone mineral density. This will be assessed as a composite outcome.	Testing bone turnover markers via serum procollagen type I N propeptide (PINP) and plasma C-terminal cross-linking telopeptide of type I collagen (CTX). Bone densitometry imaging.	Serum/plasma/urine - at screening and at 6 and 12 months on treatment. Bone densitometry imaging - at screening and 12 months on treatment.

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References

Clinical Trials Gov: Working Out M0 Bipolar Androgen Therapy