Enzalutamide With Lu PSMA-617 Versus Enzalutamide Alone in Men With Metastatic Castration-resistant Prostate Cancer

Study Overview
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Brief Summary
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This phase 2 randomised clinical trial will investigate the activity and safety of adding Lu-PSMA to enzalutamide in patients with metastatic castrate resistant prostate cancer (mCRPC) not previously treated with chemotherapy.

Detailed Description
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This is an open label, randomised, stratified, 2-arm, multicentre phase 2 clinical trial recruiting 160 participants over 12 months and followed until 150 events occurred (approximately another 18 months). Participants will be randomised to enzalutamide or enzalutamide and Lu-PSMA in a 1:1 ratio. A minimisation approach will be used to minimise chance imbalances across the following stratification factors: study site, volume of disease (>20 versus ≤20 sites of disease measured on 68Ga-PSMA PET/CT), prior treatment with early docetaxel for castration- sensitive disease (yes vs no), and prior treatment with early abiraterone for castration-sensitive disease (yes vs no).

Official Title
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ENZA-p: A Randomised Phase II Trial Using PSMA as a Therapeutic Agent and Prognostic Indicator in Men With Metastatic Castration-resistant Prostate Cancer Treated With Enzalutamide (ANZUP 1901)

Conditions
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Metastatic Castration-Resistant Prostate Cancer

Intervention / Treatment
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* Drug: Lu-PSMA
* Drug: Enzalutamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males aged 18 or older with metastatic adenocarcinoma of the prostate defined by: Documented histopathology of prostate adenocarcinoma (no features of neuroendocrine carcinoma) OR Metastatic disease typical of prostate cancer Castration-resistant prostate cancer (defined as disease progressing despite castration by orchiectomy or ongoing luteinising hormone-releasing hormone agonist or antagonist). Progressive disease with rising PSA defined by PCWG3 criteria (sequence of 2 rising values at a minimum of 1-week intervals) AND PSA ≥ 5 ng/mL. At least 2 of the following risk factors for early treatment failure with enzalutamide: LDH ≥ ULN ALP ≥ ULN Albumin <35 g/L De novo metastatic disease (M1) at initial diagnosis * <3 years since initial diagnosis >5 bone metastases * Visceral metastases * PSA doubling time <84 days Pain requiring opiates for >14 days Prior treatment with abiraterone * Based on conventional imaging (CT and/or bone scan) Target or non-target lesions according to RECIST 1.1 Significant PSMA avidity on 68Ga-PSMA PET/CT, defined as SUVmax >15 at a single site (regardless of lesion size) and SUV max >10 at sites of disease ≥10mm (unless subject to factors explaining a lower uptake, e.g. respiratory motion, reconstruction artefact) ECOG performance status 0-2 Adequate renal function: - Creatinine clearance ≥ 40mL/ min Adequate liver function: Bilirubin < 1.5 x upper limit of normal (ULN) (or if bilirubin is between 1.5 - 2x ULN, must have a normal conjugated bilirubin) AST or ALT ≤ 2.0 x ULN (or ≤ 5.0 x ULN in the presence of liver metastases) Adequate bone marrow function: Platelets ≥ 100 x109/L Haemoglobin ≥ 90g/L (no red blood cell transfusion in last 4 weeks) Neutrophils > 1.5 x109/L Estimated life expectancy > 12 weeks Study treatment both planned and able to start within 21 days of randomisation Willing and able to comply with all study requirements (including both treatments: enzalutamide and Lu-PSMA), and all required study assessments Signed, written, informed consent Exclusion Criteria: Prostate cancer with known significant sarcomatoid, or spindle cell, or neuroendocrine small cell components, or metastasis of other cancer to the prostate 68Ga-PSMA PET/CT SUVmax < 10 at a site of measurable disease > 10mm Prior treatment with enzalutamide, darolutamide, or apalutamide. Prior treatment with abiraterone is allowed. Prior treatment with any PSMA-targeted radiotherapy Prior chemotherapy for mCRPC. Prior docetaxel in castration-sensitive setting is permitted History of another malignancy within 5 years prior to randomisation except for non-melanomatous carcinoma of the skin; or, adequately treated, non-muscle-invasive urothelial carcinoma of the bladder (i.e. Tis, Ta and low grade T1 tumours) Concurrent illness, including severe infection that may jeopardise the ability of the participant to undergo the procedures outlined in this protocol with reasonable safety Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule, including alcohol dependence or drug abuse Men in sexual relationships with women of reproductive potential who are not willing/able to use medically acceptable forms of barrier contraception History of: seizure or any condition that may predispose to seizure (e.g. prior cortical stroke or significant brain trauma) loss of consciousness or transient ischemic attack within 12 months of randomization significant cardiovascular disease within the last 3 months: including myocardial infarction, unstable angina, congestive heart failure (NYHA grade II or greater, see Appendix 4), ongoing arrhythmias of Grade > 2, thromboembolic events (e.g. deep vein thrombosis, pulmonary embolism). Chronic stable atrial fibrillation on stable anticoagulant therapy is allowed

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lu-PSMA + Enzalutamide<br>Lu-PSMA - 7.5 GBq (± 10%): doses 1 and 2 (Days 15 and 57). Doses 3 and 4 (Days 113 and 169) will be given following result of PSMA PET/CT scans at Day 92. Enzalumatide - 160 mg (four 40 mg capsules): daily until participant is no longer clinically benefiting, or experiences unacceptable toxicity. | Drug: Lu-PSMA<br>* Patients will be given 7.5 GBq of Lu-PSMA in 4 doses. Dose 1 and 2 on Days 15 and 57. Doses 3 and 4 (Days 113 and 169) will be given following result of 68Ga-PSMA PET/CT at Day 92. Treatment administered every 6 weeks, x 4 cycles.<br>* Other names: 177Lutetium -PSMA 617 also referred to as 177Lu-PSMA;Drug: Enzalutamide<br>* 160 mg (four 40 mg capsules) daily.<br>* Other names: Xtandi;|
| Active Comparator: Enzalutamide<br>Enzalutamide - 160 mg (four 40 mg capsules): daily until participant is no longer clinically benefiting, or experiences unacceptable toxicity. | Drug: Enzalutamide<br>* 160 mg (four 40 mg capsules) daily.<br>* Other names: Xtandi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prostate Specific Antigen (PSA) Progression-Free Survival | PSA progression is defined as a rise in PSA by more than or equal to 25% AND more than or equal to 2 ng/mL above the nadir (lowest PSA point). This needs to be confirmed by a repeat PSA performed at least 3 weeks later. | Date of randomisation to the date of first evidence of PSA progression - assessed up to study completion, approximately 4 years from recruitment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiographic Progression-Free Survival | Radiographic progression-free survival is defined as the interval from the date of randomisation to the date of first evidence of radiographic progression on imaging, or the date of last known follow-up without progression. | Date of randomisation to the date of first evidence of radiographic progression on imaging. Assessed every 12 weeks through study completion, approximately 4 years from start of recruitment. | 
| Prostate Specific Antigen (PSA) response rate | PSA response rate is defined as the proportion of participants in each group with a PSA reduction of 50% or more from baseline. | Date of randomisation through study completion, approximately 4 years from start of recruitment. Early rises in PSA prior to 12 weeks will be disregarded in determining PSA response | 
| Pain response and Progression-Free Survival | Pain is measured using the McGill-Melzack Present Pain Intensity scale (PPI). Pain Response is defined as a reduction of 2 or more points for participants with a baseline PPI score of 2 or more. Pain progression is defined as and an increase of 1 or more points in the nadir PPI score. Pain Response is defined as a reduction of 2 or more points for participants with a baseline PPI score of 2 or more. Pain progression is defined as and an increase of 1 or more points in the nadir PPI score. | Date of randomisation through study completion, approximately 4 years from start of recruitment | 
| Clinical Progression-Free Survival | Clinical progression is defined by progression on imaging, development of symptoms attributable to cancer progression, the need for radiotherapy to new metastases or initiation of other anticancer treatment for prostate cancer. | Date of randomisation to the date of first clinical evidence of disease progression or death from any cause. Assessed up to study completion approximately 4 years from recruitment. | 
| Aspects of Health-related Quality of life (HRQL) | The European Organisation for Research and Treatment of Cancer (EORTC) core quality of life questionnaire includes five functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and nausea and vomiting), and a global health and quality-of-life scale to assess HRQL in cancer patients. The Patient DATA form is a simple, multi-item quality of life instrument based on 11-point numeric rating scales for a range of relevant symptoms and functions. It combines cancer specific items from the UBQ-C, GLQ-8 and LASA cancer-specific quality of life instruments. The Fear of Cancer Progression form is a short questionnaire assessing possible future concerns related to the participant's illness. | Assessed every 4-6 weeks, through study completion, approximately 4 years from recruitment. | 
| Frequency and Severity of Adverse Events | The Common Terminology Criteria for Adverse Events (CTCAE) v5.0 will be used to classify and grade the intensity of adverse events during study treatment. | Through study completion, approximately 4 years from recruitment. |