AMPLITUDE

Pre-screening eligibility criteria for participants who do not have prior results available from either a local test or sponsor’s commercial tumour tissue test:

1. Pre- screening informed consent obtained (written or remote/virtual).

2. Aged over 16 years of age.

3. Histologically confirmed metastatic prostate adenocarcinoma.

4. Can provide a tumour tissue (previously archived or fresh) sample for determination of deleterious germline or somatic HRR gene mutations. Tumour tissue will only be collected at pre-screening if no local or prior sponsor-approved test result is available.

Each potential participant must satisfy all of the following criteria to be randomised into the study following pre-screening:

1. 16 years of age or older.

2. Diagnosis of prostate adenocarcinoma.

3. Willing to provide an archival tumour tissue sample or a fresh tumour tissue sample. If germline positive for deleterious germline or somatic HRR gene mutations, an archived or fresh tumour tissue sample is not required.

4. Metastatic disease documented by at least 1 bone lesion(s) on 99mTc bone scan. Participants with a single bone lesion must have confirmation of bone metastasis by CT or MRI.

5. Must have at least one of the deleterious germline or somatic HRR gene mutations listed in the study protocol.

6. Eastern Cooperative Oncology Group Performance Status (ECOG PS) grade less than 2.

7. Androgen deprivation therapy (either medical or surgical castration) must have been started more than 14 days prior to randomisation and willing to continue through the treatment phase. Participants who start a GnRH agonist less than 28 days prior to randomisation will be required to take a first-generation anti-androgen for more than 14 days prior to randomisation. The anti-androgen must be discontinued prior to randomisation.

8. Participants who have received prior docetaxel treatment must meet the following criteria:

a. Received a maximum of 6 cycles of docetaxel therapy for mCSPC.

b. Received the last dose of docetaxel less than 2 months prior to randomisation.

c. Maintained a response to docetaxel of stable disease or better, by investigator assessment of imaging and PSA, prior to randomisation.

9. Other allowed prior therapy for mCSPC:

a. Maximum of 1 course of radiation or surgical intervention to manage symptoms of prostate cancer. Radiation with curative intent is not allowed. Radiation must be completed prior to randomisation.

b. Less than 6 months of ADT prior to randomisation.

c. 30 days of AA-P allowed if required.

10. Allowed prior treatments for localised prostate cancer (all treatments must have been completed at least 1 year prior to randomisation):

a. Less than or equal to 3 years total of ADT

b. All other forms of prior therapies including radiation therapy, prostatectomy, lymph node dissection, and systemic therapies.

11. Clinical laboratory values at Screening:

a. Absolute neutrophil count greater than or equal to 1.5 x 109/L

b. Haemoglobin greater than or equal to 9.0 g/dL, independent of transfusions for at least 28 days

c. Platelet count greater than or equal to 100 x 109/μL

d. Serum albumin greater than or equal to 3.0 g/dL

e. Creatinine less than 2 x upper limit of normal (ULN)

f. Serum potassium greater than or equal to 3.5 mmol/L

g. Serum total bilirubin less than or equal to 1.5 × ULN or direct bilirubin ≤ 1 x ULN.

(Note: In participants with Gilbert’s syndrome, if total bilirubin is more than 1.5 × ULN, measure direct and indirect bilirubin, and if direct bilirubin is less than or equal to 1.5 × ULN, participant may be eligible)

h. AST or ALT less than or equal to 3 × ULN.

12. Able to swallow the study medication tablets whole.

13. Must provide informed consent (written or remote/virtual) indicating that he understands the purpose of, and procedures required for, the study and is willing to participate in the study including providing a DNA sample.

14. While on study medication and for 3 months following the last dose of study medication, a male participant must wear a condom when engaging in any activity that allows for passage of ejaculate to another person. Male participants should also be advised of the benefit for a female partner to use a highly effective method of contraception as condom may break or leak. Highly effective methods of contraception include:

a. established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device or intrauterine system;

b. barrier methods: condom with spermicidal foam/gel/film/cream/suppository or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.

15. A male participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 3 months after receiving the last dose of study medication. 

Any potential participant who meets any of the following criteria will be excluded from participating in the study:

1. Pathological finding consistent with small cell ductal or neuroendocrine carcinoma of the prostate.

2. Prior treatment with a PARP inhibitor.

3. Prior AR-targeted therapy (for e.g. ketoconazole for prostate cancer, apalutamide, enzalutamide, darolutamide), immunotherapy, or radiopharmaceutical agents with the exception of only 30 days of AA-P allowed prior to randomisation.

4. Initiation of treatment with a bisphosphonate or denosumab for the management of bone metastasis less than 28 days prior to randomisation.

5. History of adrenal dysfunction.

6. Long-term use of systemically administered corticosteroids (> 5 mg of prednisone or the equivalent) during the study is not allowed. Short-term use (≤ 4 weeks, including taper) and locally administered steroids (for e.g. inhaled, topical, ophthalmic, and intra-articular) are allowed, if clinically indicated.

7. Active malignancies (i.e. progressing or requiring treatment change in the last 24 months) other than the disease being treated under study. The only allowed exceptions are:

a. non-muscle invasive bladder cancer;

b. skin cancer (non-melanoma or melanoma) treated within the last 24 months that is considered completely cured;

c. breast cancer – adequately treated lobular carcinoma in situ or ductal carcinoma in situ;

d. malignancy that is considered cured with minimal risk of recurrence.

8. History or current diagnosis of MDS/AML.

9. Current evidence within 6 months prior to randomisation of any of the following: severe/unstable angina, myocardial infarction, symptomatic congestive heart failure, clinically significant arterial or venous thromboembolic events (e.g. pulmonary embolism), or clinically significant ventricular arrhythmias.

10. Presence of sustained uncontrolled hypertension (systolic blood pressure greater than 160 mm Hg or diastolic blood pressure greater than 100 mm Hg). Participants with a history of hypertension are allowed, provided that blood pressure is controlled to within these limits by an antihypertensive treatment.

11. Known allergies, hypersensitivity, or intolerance to the excipients of niraparib, AA, or niraparib/AA FDC (refer to the IBs for niraparib and AA).

12. Current evidence of any medical condition that would make prednisone use contraindicated.

13. Received an investigational intervention (including investigational vaccines) or used an invasive investigational medical device within 30 days before the planned first dose of study medication.

14. Participants who have had the following ≤ 28 days prior to randomisation:

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

b. Hematopoietic growth factors;

c. Major surgery (sponsor should be consulted regarding what constitutes major surgery).

15. Known active hepatitis B virus (for e.g. hepatitis B surface antigen reactive) or active hepatitis C virus (HCV; for e.g. HCV ribonucleic acid [RNA] [qualitative] is detected).

16. Human immunodeficiency virus positive participants with 1 or more of the following:

a. Not receiving highly active antiretroviral therapy or on antiretroviral therapy for less than 4 weeks.

b. Receiving antiretroviral therapy that may interfere with the study medication (consult the sponsor for review of medication prior to enrolment).

c. A change in antiretroviral therapy within 6 months of the start of screening (except if, after consultation with the sponsor on exclusion criterion 16.b, a change is made to avoid a potential drug-drug interaction with the study medication).

d. CD4 count less than 350 at screening.

e. An acquired immunodeficiency syndrome-defining opportunistic infection within 6 months of the start of screening.

f. Human immunodeficiency virus load more than 400 copies/mL. 

Research Nurse: Catherine Walmsley (x8475) Catherine.Walmsley@lthtr.nhs.uk

Administrator: Aaisha Khan (x8475)