A Randomised Controlled Platform Trial Testing Treatments in Metastatic Hormone Sensitive Prostate Cancer

Prostate Cancer Metastatic Clinical Trial

— STAMPEDE2  

Official title:

Studying Treatments in Patients Receiving Androgen Deprivation Therapy (ADT) and Androgen Receptor Signalling Inhibitors (ARSI) for Metastatic Prostate Cancer: Evaluation of Drug and Radiation Efficacy: A 2nd Multi-arm Multi-stage Randomised Controlled Trial (STAMPEDE2).

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06320067
• Other study ID #: PR12
• Secondary ID: 1006437
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: April 2024
• Est. completion date: March 2034

Study information

• Verified date: March 2024
• Source: University College, London
• Contact: Pamela Niem
• Phone: +442076704921
• Email: mrcctu.stampede2[@]ucl.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

STAMPEDE2 is a clinical trial comparing three new treatments with standard of care in people with prostate cancer that has spread to other parts of the body and is responsive to hormone therapy. People from all backgrounds and ethnicities are encouraged to take part and multiple hospitals across the UK are involved. University College London is running the trial. Each comparison within the trial has its own control arm where people get the best standard of care (Arm A) versus a research arm where a new treatment is added to standard of care. Participants are allocated to an arm by a computerised system with a 50% chance of getting the research treatment. Comparison S: Arm A versus Arm S (Stereotactic Ablative Body Radiotherapy (SABR)) - Tests whether giving targeted doses of radiotherapy (SABR) to parts of the body where the cancer has spread slows the spread of the cancer and improves survival. 2476 people will be in this comparison. Comparison P: Arm A versus Arm P (PSMA-Lutetium (177Lu-PSMA-617)) - Tests whether giving a radioactive material (177Lu-PSMA-617) that targets prostate cancer cells slows the spread of the cancer and improves survival. 1756 people will be in this comparison. Comparison N: Arm A(N) versus Arm N (Niraparib-Abiraterone Acetate+Prednisolone (Nira-AA+P)) - Tests whether giving a new drug (Nira-AA+P) slows the spread of the cancer and improves survival. Only people with certain genetic changes in their tumour sample can take part in Comparison N. 682 people will be in this comparison. Participants may be able to take part in more than one comparison. All participants will be followed up with scans and tests to monitor their cancer. Doctors will check for any side effects from the treatments. Treatments will be stopped if side effects are serious, or people no longer wish to take the treatments.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 8000
• Est. completion date: March 2034
• Est. primary completion date: April 2031
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

4.4. ELIGIBILITY FOR REGISTRATION INTO THE STAMPEDE2 TRIAL Inclusion criteria I. At least 18 years old II. Histological confirmation of prostate adenocarcinoma or a strong clinical suspicion of prostate cancer with a plan to confirm the diagnosis formally before any future randomisation. III. Confirmation of metastatic site(s) on CT/MRI or bone scan. Patients with metastatic

disease meeting any of the following criteria are eligible:

• Metastatic disease to the bone (in any distribution) visible on 99Tc-Bone Scan
• Non-regional lymph node metastases of any size or distribution. Lymph nodes that are only visible on PET will not be eligible as sites of metastasis. Note: If lymph nodes are the only site of metastases, then at least one must be at least 1.5cm in short axis AND outside of the pelvis.
• Visceral metastases of any size or distribution IV. De novo presentation or, if relapsed, all hormonal treatments (ADT and ARSI) will have been completed =1 year prior to any future randomisation into any of the comparisons and have received =1 year total of ADT. This will be checked again at randomisation. V. Long-term androgen deprivation therapy (ADT) has started or there is an intention to start for a minimum of 2 years. VI. WHO performance status 0-2 or if WHO Performance Status 3, deemed to be due to metastatic burden and expected to improve with ADT. Note: Improvement to WHO status 0-2 will be checked again at randomisation into any subsequent comparison. Note: For WHO performance status definitions see Appendix 1. VII. Willing and able to comply with trial treatments. VIII. Patient has signed informed consent form for registration into the STAMPEDE2 Trial platform. Exclusion criteria I. Clinically and pathologically overt small cell carcinoma. II. Metastatic brain disease or leptomeningeal disease. III. Any active malignancies (i.e., progressing or requiring any treatment in the previous 36 months) other than prostate cancer (except non-muscle invasive bladder cancer; non-melanomatous skin cancer or a malignancy that is considered cured with minimal risk of recurrence). IV. Any other medical condition that in the investigator's opinion means the participant is unfit or unsuitable for long-term ARSI or the trial treatments in the comparison for which they are being considered. 4.5. ELIGIBILITY FOR BIOMARKER TESTING FOR COMPARISON N In addition to the general eligibility criteria in Section 4.4 participants need to meet the following eligibility criteria for central biomarker testing for Comparison N: Inclusion criteria I. Confirm you have checked that there is adequate time for the central biomarker test result to be returned so that randomisation into Comparison N would occur no more than 6 months after starting ADT. II. Have a tumour block that is available for transferring to the Central Biomarker Testing Laboratory. The location details for this block will be needed at the block request stage. Where patients have a confirmed alteration in one of the genes in the biomarker panel using a local accredited NHS biomarker test, this can be used to assess biomarker status and if positive, the participant can proceed to eligibility assessment for Comparison N. Permission to access the patient's tissue is still required for any central confirmatory testing that might be required. III. Patient has provided signed informed consent for use of tissue for testing. Exclusion criteria I. Patient has started ARSI therapy. If this has already started, patients will not be eligible for Comparison N or central biomarker testing, but they can still be considered for Comparisons S and P. II. Contraindications to niraparib, abiraterone acetate, prednisolone or apalutamide according to the reference safety information. 4.6. ELIGIBILITY CRITERIA FOR COMPARISON S TESTING SABR Patients who meet the eligibility criteria in Section 4.4 can be considered for the SABR comparison. Recruiting sites will assess metastatic disease burden using conventional imaging (baseline Tc-99m bone scan and CT/MRI scans) to assess number of metastatic bone and non-regional lymph node foci, and presence of visceral metastases. Patients will be classified as either 'SABR-eligible' or 'SABR-ineligible' using the following definition. Definition of SABR-eligible disease:

Patients will be classified as SABR-eligible if they meet all the following criteria:

• 1-5 metastatic lesions (including either bone and/or non-regional lymph node sites) using conventional imaging.
• Clinician determination that metastatic lesions are considered suitable for SABR on technical grounds (such as proximity of dose limiting normal tissue or tumour volume).
• Absence of visceral metastases. Otherwise, patients will be classified as SABR-ineligible. In addition to the general registration eligibility criteria in Section 4.4, they need to meet all the following criteria for entry into Comparison S: Inclusion criteria I. Patient still meets all eligibility criteria for registration in Section 4.4 II. Histological confirmation of prostate adenocarcinoma III. Newly diagnosed (de novo) metastatic disease that is considered eligible for SABR according to the definition in Section 4.6 IV. Patient has started ADT and randomisation is =12 weeks since the start of ADT V. WHO performance status 0-2 (see Appendix 1) VI. Patient has provided signed informed consent for participation in Comparison S Exclusion criteria I. Patient has relapsed prostate cancer II. Prior radical treatment to the prostate (e.g., radical surgery and/or radiotherapy). III. Intracranial metastatic disease. IV. Prior treatment to a metastatic site (e.g., radiotherapy, surgery or RFA). V. Significant or progressive neurological deficit such that emergency (within 24 hours) surgery or radiation required (e.g., metastatic spinal cord compression, or impingement of the cord or any other clinical scenario whereby urgent radiotherapy to the spine is required). VI. Any condition or co-morbidities that, in the judgement of the clinician, preclude

procedures required to facilitate radiotherapy delivery e.g:

1. Disease staging and follow-up.

2. Radiotherapy planning procedures. VII. Any condition or co-morbidities that, in the judgement of the clinician, preclude the safe delivery of radiotherapy to the prostate (+/- pelvic lymph nodes) and/or metastases e.g., inflammatory bowel disease, significant systemic connective tissue disorder, radiological evidence of idiopathic pulmonary fibrosis) VIII. Active malignancy other than prostate cancer within the last 36 months. 4.7. ELIGIBILITY CRITERIA FOR COMPARISON P TESTING 177LU-PSMA-617 In addition to the general eligibility criteria in Section 4.4, patients need to meet the following criteria for entry into Comparison P: Inclusion criteria I. Patient still meets all eligibility criteria for registration in Section 4.4. II. Histological confirmation of prostate adenocarcinoma. III. Patient meets the definition of SABR ineligible disease in Section 4.6. IV. Patients must have adequate organ function as indicated by blood tests within 8 weeks prior to randomisation: Bone marrow function

1. ANC =1.5 x 109/L

2. Platelets =100 x 109/L

3. Haemoglobin =9g/dL, independent of transfusions for at least 28 days Hepatic function

1. Total bilirubin =2 x ULN. For patients with Gilbert's Syndrome =3 x ULN is permitted.

2. AST and/or ALT performed with all results =3 × ULN or =5 x ULN for patients with liver metastasis Renal Function

1. EGFR =50 mL/min/1.73m2 calculated using the MDRD formula

2. Albumin =25g/L V. Patient has started ADT and randomisation is =12 weeks since start of current ADT. VI. If relapsed, prior LHRH agonist/antagonist with or without first generation anti-androgen use in the adjuvant/neo-adjuvant setting, hormone treatment must have been discontinued >12 months prior to randomisation AND must not have exceeded 12 months of therapy AND must not have shown disease progression within 12 months of completing adjuvant/neo-adjuvant therapy. VII. WHO performance status 0-2 (see Appendix 1). VIII. Patient has provided signed informed consent for participation in Comparison P. Exclusion criteria

I. Prior treatment with any of the following:

1. Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223

2. PSMA-targeted radioligand therapy II. Symptomatic cord compression, or clinical/radiological findings indicative of impending cord compression. III. Any condition that precludes raised arms position. IV. Unmanageable bladder outflow obstruction or urinary incontinence. Note: bladder outflow obstruction or urinary incontinence which is manageable and controlled with best available standard of care (incl. drainage, pads) is permitted). V. If taking part in the Imaging Substudy, contraindication to MRI (e.g., pacemakers, except MRI compatible pacemakers). 4.8. ELIGIBILITY CRITERIA FOR COMPARISON N TESTING NIRAPARIB-AA+P In addition to the general registration eligibility criteria in Section 4.4, patients need to meet the following criteria for randomisation into Comparison N: Inclusion criteria I. Patient still meets all eligibility criteria for registration in Section 4.4 of master protocol. II. Histological confirmation of prostate adenocarcinoma. III. Biomarker-positive status as defined in Section 9.4 of master protocol. IV. Patients must have adequate organ function as indicated by blood tests within 8 weeks

prior to randomisation:

1. Absolute neutrophil count =1.5 x 109/L

2. Haemoglobin =9.0 g/dL, independent of transfusions for at least 28 days

3. Platelet count =100 x 109/µL

4. Serum albumin =30 g/L

5. Creatinine =2 x upper limit of normal (ULN)

6. Serum potassium =3.5 mmol/L

7. Serum total bilirubin =1.5× ULN or direct bilirubin =1 x ULN (Note: In patients with Gilbert's syndrome where total bilirubin is >1.5 × ULN, direct bilirubin of =1.5 × ULN is permitted V. AST and/or ALT performed with all results =3 × ULN VI. Patient has commenced ADT, with a start date of less than 6 months prior to randomisation into Comparison N. VII. If relapsed disease, prior LHRH agonist/antagonist with or without first generation anti-androgen use in the adjuvant/neo-adjuvant setting, hormone treatment must have been discontinued >12 months prior to randomisation AND must not have exceeded 12 months of therapy AND must not have shown disease progression within 12 months of completing adjuvant/neo-adjuvant therapy. VIII. Has not received prior docetaxel treatment for prostate cancer or meets ALL of the

following criteria:

1. Received =6 cycles of docetaxel therapy

2. Received the last dose of docetaxel =3 weeks prior to starting on IMP and =3 months prior to randomisation

3. Maintained a response to docetaxel of stable disease or better, in the view of the investigator based upon imaging and/or PSA, prior to randomisation IX. WHO performance status 0-2 (see Appendix 1 for WHO performance criteria). X. Able to swallow the trial treatment tablets whole (clinician determined). XI. Patient has provided signed informed consent for participation in Comparison N. Exclusion criteria I. Prior treatment outside the STAMPEDE2 trial with a poly ADP ribose polymerase (PARP) inhibitor, radiopharmaceutical or any chemotherapy for prostate cancer other than docetaxel. II. History of adrenal dysfunction. III. History or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML). IV. Known allergies, hypersensitivity, or intolerance to the excipients of AA, or Nira-AA DAT (refer to the IBs for Nira-AA DAT and AA). V. Currently taking and planning to continue any medications that are contraindicated for the trial IMPs of Apalutamide, Abiraterone Acetate or Niraparib as described in the Comparison N appendix. VI. Current evidence of any medical condition that would make prednisolone use contraindicated. VII. Presence of sustained uncontrolled hypertension. At randomisation, sites will be asked to provide one blood pressure reading (systolic <160 mmHg and diastolic blood pressure reading <100 mmHg) recorded within the 8 weeks prior to randomisation. VIII. Received an investigational intervention not related to the STAMPEDE2 trial (including investigational vaccines) or used an invasive investigational medical device within 30 days prior to randomisation. IX. Patient has commenced ARSI therapy (including abiraterone acetate and prednisolone, enzalutamide, apalutamide or darolutamide).

X. Patients who have had any of the following =28 days prior to randomisation:

1. A transfusion (platelets or red blood cells);

2. Hematopoietic growth factors;

3. Surgery requiring general anaesthetic XI. Known active hepatitis B virus (e.g., hepatitis B surface antigen reactive) or active hepatitis C virus (HCV; e.g., HCV ribonucleic acid [RNA] [qualitative] is detected).

XII. Known HIV infection and any one of the following:

1. AIDS defining opportunistic infection within 6 months prior to randomisation

2. HAART or ART regimen non-compatible with the drugs of the study due to drug-drug interaction with Niraparib (e.g., Protease inhibitors, cobicistat, efavirenz, nevirapine, etravirine, doravirine and rilpivirine)

3. CD4 count below 300/mm3 within the 8 weeks prior to randomisation.

4. Detectable viral load within the 8 weeks prior to randomisation.

Related Conditions & MeSH terms

• Prostate Cancer Metastatic
• Prostatic Neoplasms

Intervention

Radiation:
• Stereotactic Ablative Body Radiotherapy (SABR)
SABR is a way of giving focused high-dose radiotherapy. SABR given with a dose fractionation schedule of 30Gy in 3-5 fractions over 1-2 weeks to up to 5 metastatic lesions in the bone and/or non-regional (extra-pelvic) lymph nodes.

Other:
• 177Lu-PSMA-617
177Lu-PSMA-617 is a nuclear medicine therapy. Patients will receive 177Lu-PSMA-617 to a dose of 7.4GBq. Each cycle will consist of 2 doses, 1 week apart (on day 1 and day 8) and will last 6 weeks. Treatment will be given for up to 3 cycles (6 doses).

Drug:
• Niraparib and Abiraterone Acetate Dual Action Tablet DAT
Combination product containing Niraparib (PARP inhibitor) and Abiraterone Acetate (ARSI). The regular-strength dual-action tablet (DAT) contains 100 mg niraparib/500mg AA per tablet. Patients take 2 tablets a day and receive a of total dose 200 mg niraparib/1000 mg AA. A low-strength DAT tablet containing 50 mg niraparib/500 mg AA may be available for participants requiring a dose reduction of niraparib.
• Abiraterone Acetate
Abiraterone Acetate is an ARSI. Single agent Abiraterone Acetate may be used in patients randomised to receive Niraparib and Abiraterone Acetate.
• Apalutamide
Apalutamide is an ARSI administered as a 240mg oral dose (four tablets taken together at the same time every day) with or without food. It is given daily in 28-day cycles.
• Androgen Deprivation Therapy (ADT)
Long-term, continuous treatment with ADT (bilateral orchidectomy, LHRH agonists or LHRH antagonists) if not previously surgically castrated. The choice of ADT is at the discretion of the investigator. This will be given as standard of care as per local guidelines.
• Androgen Receptor Signalling Inhibitor (ARSI)
Second generation ARSI (Abiraterone Acetate and Prednisolone [AA+P], Enzalutamide, Apalutamide or Darolutamide). This will be given as standard of care as per local guidelines. Abiraterone acetate will be administered as a single 1000mg once daily dose (4 tablets to be taken together once a day) with prednisolone 5mg once daily to prevent secondary mineralocorticoid excess. Enzalutamide will be administered as a 160mg oral dose (four capsules taken together at the same time every day) with or without food. Enzalutamide is administered daily in 28-day cycles. Apalutamide will be administered as 240mg oral dose (four tablets taken together at the same time every day) with or without food. Apalutamide is administered daily in 28-day cycles. Patients require thyroid function monitoring. Darolutamide will be administered as 600mg oral dose (two 300mg tablets taken together) with or without food. Darolutamide is administered twice daily in 28-day cycles.

Radiation:
• Local Radiotherapy
Either 36.25Gy given in 5 fractions over 1-2 weeks to prostate or 60Gy in 20 fractions over 4 weeks to prostate (± 47Gy in 20 fractions to pelvic lymph nodes ± 51Gy in 20 fractions boost to involved nodes).

Drug:
• Prednisolone
Prednisolone should also be administered 5mg daily using local pharmacy prescribing.
• Docetaxel
Maximum of 6 cycles every 3 weeks may be given at a dose of 75mg/m2 by IV infusion.

Locations

Country	Name	City	State
n/a

Sponsors (4)

Lead Sponsor	Collaborator
University College, London	Cancer Research UK, Janssen Pharmaceutica NV, Novartis

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Radiographic Progression-Free-Survival (rPFS)	rPFS is defined as the time from randomisation to progression of metastatic prostate cancer confirmed by radiographic imaging or death from any cause. The definition for rPFS requires at least one of the following four criteria to be met: Radiological metastatic progression by RECIST v1.1,; Progression of bone metastases as defined by PCWG3,; Symptomatic skeletal-related events secondary to cancer progression,; Death from any cause.; Note: Dual-primary outcomes of radiographic Progression-Free-Survival (rPFS) and Overall Survival (OS).; The final reporting times of rPFS for each comparison below will depend on the recruitment rates and the accuracy of assumed median survival times in the sample size calculations.	Final analysis for each comparison triggered when adequate number of rPFS events have occurred in control arm of each comparison. Anticipate final reporting for rPFS in Comparison S: 58 months from FPFV, P: 42 months from FPFV and N: 65 months from FPFV.
Primary	Overall Survival (OS)	OS is defined as time from randomisation to death from any cause.; Note: Dual-primary outcomes of radiographic Progression-Free-Survival (rPFS) and Overall Survival (OS).; The final reporting times of OS for each comparison below will depend on the recruitment rates and the accuracy of assumed median survival times in the sample size calculations. Please note that a closed test approach has been used for OS as a dual primary outcome. Continuation of FU for OS will be dependent on observing a significant result for rPFS.	Final analysis for each comparison triggered when adequate number of death events have occurred in control arm of each comparison. Anticipate final reporting for OS in Comparison S: 94 months from FPFV, P: 62 months from FPFV and N: 177 months from FPFV.
Secondary	Failure-Free Survival (FFS)	Time from randomisation until the first of: Biochemical progression; Local progression; Pelvic Lymph node progression; Distant metastases development or progression; Skeletal Related Event (where confirmed disease progression); Death from prostate cancer	Up to 10 years from randomisation. FFS is declared as a secondary outcome and is not part of sample size calculations, nor timelines for the study.
Secondary	Prostate cancer specific survival (PCSS)	Time from randomisation to death from prostate cancer.	Up to 10 years from randomisation. PCSS is declared as a secondary outcome and is not part of the sample size calculations, nor timelines for the study.
Secondary	Safety through reporting of SAEs		S: until 6 months after randomisation; P: until 6 months after randomisation or 40 days after completion or permanent discontinuation of an IMP 177Lu-PSMA-617 (whichever is furthest); N: until 30 days after permanent discontinuation of an IMP
Secondary	Toxicity using CTCAE classification and reporting of all Adverse Events that are = grade 3 or grade 1 and 2 leading to a change in trial treatment		All safety and toxicity data will be presented by randomised group. The exact nature of this will be pre-specified in the statistical analysis plan that is still in development.
Secondary	Compliance with randomised allocation. Formal definitions for compliance with treatment will be pre-specified in the statistical analysis plan. This is still in development.		Randomisation until death or end of trial treatment (up to 10 years from randomisation).
Secondary	EQ-5D-5L questionnaire for QoL and cost effectiveness assessment		From date of randomisation until death or end of trial, whichever came first (up to 10 years from randomisation). The end of the trial will be determined by the timelines described in the primary outcomes section.