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

NCT ID: NCT04419402

Last Updated: 2024-02-07

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 162 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-08-17
• Study Completion Date: 2025-01-01

Brief Summary

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

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).

Conditions

Metastatic Castration-Resistant Prostate Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Lu-PSMA + Enzalutamide

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.

Group Type: EXPERIMENTAL

Lu-PSMA

Intervention Type: DRUG

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.

Enzalutamide

Intervention Type: DRUG

160 mg (four 40 mg capsules) daily.

Enzalutamide

Enzalutamide - 160 mg (four 40 mg capsules): daily until participant is no longer clinically benefiting, or experiences unacceptable toxicity.

Group Type: ACTIVE_COMPARATOR

Enzalutamide

Intervention Type: DRUG

160 mg (four 40 mg capsules) daily.

Interventions

Lu-PSMA

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.

Intervention Type: DRUG

Enzalutamide

160 mg (four 40 mg capsules) daily.

Intervention Type: DRUG

Other Intervention Names

177Lutetium -PSMA 617 also referred to as 177Lu-PSMA; Xtandi

Eligibility Criteria

Inclusion Criteria

1. 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

2. Castration-resistant prostate cancer (defined as disease progressing despite castration by orchiectomy or ongoing luteinising hormone-releasing hormone agonist or antagonist).

3. 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.

4. 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)

5. Target or non-target lesions according to RECIST 1.1

6. 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)

7. ECOG performance status 0-2

8. Adequate renal function:

• Creatinine clearance ≥ 40mL/ min

9. 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)

10. 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

11. Estimated life expectancy > 12 weeks

12. Study treatment both planned and able to start within 21 days of randomisation

13. Willing and able to comply with all study requirements (including both treatments: enzalutamide and Lu-PSMA), and all required study assessments

14. Signed, written, informed consent

Exclusion Criteria

1. Prostate cancer with known significant sarcomatoid, or spindle cell, or neuroendocrine small cell components, or metastasis of other cancer to the prostate

2. 68Ga-PSMA PET/CT SUVmax < 10 at a site of measurable disease > 10mm

3. Prior treatment with enzalutamide, darolutamide, or apalutamide. Prior treatment with abiraterone is allowed.

4. Prior treatment with any PSMA-targeted radiotherapy

5. Prior chemotherapy for mCRPC. Prior docetaxel in castration-sensitive setting is permitted

6. 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)

7. Concurrent illness, including severe infection that may jeopardise the ability of the participant to undergo the procedures outlined in this protocol with reasonable safety

8. 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

9. Men in sexual relationships with women of reproductive potential who are not willing/able to use medically acceptable forms of barrier contraception

10. History of:

1. seizure or any condition that may predispose to seizure (e.g. prior cortical stroke or significant brain trauma)

2. loss of consciousness or transient ischemic attack within 12 months of randomization

3. 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

National Health and Medical Research Council, Clinical Trials Centre

UNKNOWN

Sponsor Role: collaborator

Prostate Cancer Research Alliance

UNKNOWN

Sponsor Role: collaborator

Endocyte

INDUSTRY

Sponsor Role: collaborator

Astellas Pharma Inc

INDUSTRY

Sponsor Role: collaborator

Australian and New Zealand Urogenital and Prostate Cancer Trials Group

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Louise Emmett, MBBS, FRACP

Role: STUDY_CHAIR

St Vincent's Hospital, Sydney

Locations

Chris O'Brien Lifehouse

Camperdown, New South Wales, Australia

St Vincents Hospital

Darlinghurst, New South Wales, Australia

St George Hospital

Kogarah, New South Wales, Australia

Liverpool Hospital

Liverpool, New South Wales, Australia

Macquarie University Hospital

Macquarie Park, New South Wales, Australia

Calvary Mater Newcastle

Newcastle, New South Wales, Australia

Northern Cancer Institute

Sydney, New South Wales, Australia

Royal Brisbane and Women's Hospital

Brisbane, Queensland, Australia

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Monash Health

Clayton, Victoria, Australia

Austin Health

Heidelberg, Victoria, Australia

Peter MacCallum Cancer Centre

Melbourne, Victoria, Australia

The Alfred Hospital

Melbourne, Victoria, Australia

Sir Charles Gairdner Hospital

Nedlands, Western Australia, Australia

Fiona Stanley Hospital

Perth, Western Australia, Australia

Countries

Australia

References

Emmett L, Papa N, Subramaniam S, Crumbaker M, Nguyen A, Joshua AM, Sandhu S, Weickhardt A, Lee ST, Ng S, Francis RJ, Goh JC, Pattison DA, Tan TH, Kirkwood ID, Ayati N, Niu C, Hofman MS, Martin AJ, Thomas H, Davis ID, Stockler MR; ENZA-p Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Prognostic and predictive value of baseline PSMA-PET total tumour volume and SUVmean in metastatic castration-resistant prostate cancer in ENZA-p (ANZUP1901): a substudy from a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2025 Sep;26(9):1168-1177. doi: 10.1016/S1470-2045(25)00339-0. Epub 2025 Jul 30.

Reference Type: DERIVED

PMID: 40752515 (View on PubMed)

Emmett L, Subramaniam S, Crumbaker M, Joshua AM, Sandhu S, Nguyen A, Weickhardt A, Lee ST, Ng S, Francis RJ, Goh JC, Pattison DA, Tan TH, Kirkwood ID, Gedye C, Rutherford NK, Kumar ASR, Pook D, Ramdave S, Nadebaum DP, Voskoboynik M, Redfern AD, Macdonald W, Krieger L, Schembri G, Chua W, Lin P, Horvath L, Bastick P, Butler P, Zhang AY, McJannett M, Thomas H, Langford A, Hofman MS, Martin AJ, Davis ID, Stockler MR; ENZA-p Trial Investigators; Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Overall survival and quality of life with [177Lu]Lu-PSMA-617 plus enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer (ENZA-p): secondary outcomes from a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2025 Mar;26(3):291-299. doi: 10.1016/S1470-2045(25)00009-9. Epub 2025 Feb 13.

Reference Type: DERIVED

PMID: 39956124 (View on PubMed)

Emmett L, Subramaniam S, Crumbaker M, Nguyen A, Joshua AM, Weickhardt A, Lee ST, Ng S, Francis RJ, Goh JC, Pattison DA, Tan TH, Kirkwood ID, Gedye C, Rutherford NK, Sandhu S, Kumar AR, Pook D, Ramdave S, Nadebaum DP, Voskoboynik M, Redfern AD, Macdonald W, Krieger L, Schembri G, Chua W, Lin P, Horvath L, Bastick P, Butler P, Zhang AY, Yip S, Thomas H, Langford A, Hofman MS, McJannett M, Martin AJ, Stockler MR, Davis ID; ENZA-p Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. [177Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 2024 May;25(5):563-571. doi: 10.1016/S1470-2045(24)00135-9. Epub 2024 Apr 12.

Reference Type: DERIVED

PMID: 38621400 (View on PubMed)

Related Links

http://www.anzup.org.au

Description: Sponsor's website

Other Identifiers

ANZUP 1901

Identifier Type: -

Identifier Source: org_study_id