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

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.


Eligibility Criteria:
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.