| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Deleterious Germline or Somatic Homologous Recombination Repair (HRR) Gene-Mutated Metastatic Castration-Sensitive Prostate Cancer (mCSPC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Deleterious Germline or Somatic Homologous Recombination Repair (HRR) Gene-Mutated Metastatic Castration-Sensitive Prostate Cancer (mCSPC) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036909 |
| E.1.2 | Term | Prostate cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To determine if niraparib, AA, plus prednisone compared with AA plus prednisone in participants with deleterious germline or somatic HRR gene-mutated
mCSPC provides superior efficacy in improving rPFS |
|
| E.2.2 | Secondary objectives of the trial |
- To assess the clinical benefit of niraparib, AA, plus prednisone compared with AA plus prednisone in participants with deleterious germline or somatic HRR gene-mutated mCSPC
- To characterize the safety profile of niraparib, AA, plus prednisone compared with AA plus prednisone in participants with deleterious germline or somatic HRR gene-mutated mCSPC |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. 18 years of age or older
2. Criterion modified per Amendment 2.
2.1. Pathological diagnosis of prostate adenocarcinoma.
3. Criterion deleted per Amendment 1.
4. Criterion modified per Amendment 2.
4.1. Metastatic disease documented by conventional imaging with CT or
MRI (for soft tissue lesions) or 99mTc bone scan (for bone lesions).
Participants with a single bone lesion on 99mTc bone scan with no other
non-nodal metastatic disease must have confirmation of bone metastasis
by CT or MRI.
a. Participants with lymph node-only disease are not eligible.
5. Criterion modified per Amendment 1.
5.1. Must have at least one of the deleterious germline or somatic HRR
gene alterations listed in Table 4.
6. Eastern Cooperative Oncology Group Performance Status (ECOG PS)
Grade ≤2.
7. Androgen deprivation therapy (either medical or surgical castration)
must have been started ≥14 days prior to randomization and
participants be willing to continue ADT through the treatment phase.
Participants who start a GnRH agonist ≤28 days prior to randomization
will be required to take a first-generation anti-androgen for ≥14 days
prior to randomization. The anti-androgen must be discontinued prior to
randomization.
8. Criterion modified per Amendment 1.
8.1. Criterion modified per Amendment 2.
8.2. 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 ≤3 months prior to randomization
c. Maintained a response to docetaxel of stable disease or better, by
investigator assessment of imaging and/or PSA, prior to randomization.
9. Criterion modified per Amendment 1.
9.1. Criterion modified per Amendment 2.
9.2. Other allowed prior therapy for mCSPC:
a. Maximum of 1 course of radiation and 1 surgical intervention for
symptomatic control of prostate cancer (eg, uncontrolled pain,
impending spinal cord compression or obstructive symptoms).
Participants with radiation or surgical interventions to all known sites of
metastatic disease will be excluded from trial participation. Radiation
must be completed prior to randomization.
b. Up to a maximum of 6 months of ADT prior to randomization.
c. Up to a maximum of 45days of AAP prior to randomization.
d. Up to a maximum of 2 weeks of ketoconazole for prostate cancer prior
to randomization.
10. Criterion modified per Amendment 2.
10.1. Allowed prior treatments for localized prostate cancer include
radical prostatectomy (with or without lymph node dissection), radiation
therapy, and other locally directed treatments to the prostate per
institutional standards of care.
a. Participants who received ADT or first-generation anti-androgens for
the treatment of localized prostate cancer
i. ADT: must have had ≤3 years total and must have completed ≥1 year
prior to randomization
ii. First-generation anti-androgen: must have had ≤3 years total and
must have completed ≥1 year prior to randomization.
11. Criterion modified per Amendment 1.
11.1. Clinical laboratory values at Screening:
a. Absolute neutrophil count ≥1.5 x 10^9/L
b. Hemoglobin ≥9.0 g/dL, independent of transfusions for at least 28
days
c. Platelet count ≥100 x 10^9/L
d. Creatinine ≤ 2 x upper limit of normal (ULN)
e. Serum potassium ≥3.5 mmol/L
f. Serum total bilirubin ≤1.5× ULN or direct bilirubin ≤1 x ULN (Note: In
participants with Gilbert's syndrome, if total bilirubin is >1.5 × ULN,
measure direct and indirect bilirubin, and if direct bilirubin is ≤1.5 ×
ULN, participant may be eligible)
g. AST or ALT ≤3 × ULN
12. Able to swallow the study medication tablets whole.
13. Criterion modified per Amendment 1.
13.1. Must sign 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. Criterion modified per Amendment 1
14.1. While on study medication and for 3 months following the last dose
of study medication, a male participant must agree to use an adequate
contraception method as deemed appropriate by the investigator and as
specified in Section 5.3. Lifestyle Considerations.
15. Criterion modified per Amendment 1
15.1. A male participant must agree not to donate sperm while on the
study treatment and for a minimum of 3 months following the last dose
of study medication. |
|
| E.4 | Principal exclusion criteria |
1. Pathological finding consistent with small cell or neuroendocrine
carcinoma of the prostate.
2. Prior treatment with a PARP inhibitor.
3. Criterion modified per Amendment 1.
3.1. Criterion modified per Amendment 2.
3.2. Prior AR-targeted therapy (eg, apalutamide, enzalutamide,
darolutamide), immunotherapy, or radiopharmaceutical agents for
prostate cancer with the Exception: allowed prior therapies are noted in
inclusion criteria 9.2.
4. Criterion deleted per Amendment 2.
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. Shortterm
use (≤4 weeks, including taper) and locally administered steroids
(eg, inhaled, topical, ophthalmic, and intra-articular) are allowed, if
clinically indicated.
7. Active malignancies (ie, 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 randomization of any of the
following: severe/unstable angina, myocardial infarction, symptomatic
congestive heart failure, clinically significant arterial or venous
thromboembolic events (ie. pulmonary embolism), or clinically
significant ventricular arrhythmias.
10. Presence of sustained uncontrolled hypertension (systolic blood
pressure >160 mm Hg or diastolic blood pressure >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
randomization:
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. Criterion was deleted per Amendment 1
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
enrollment).
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 <350 at screening.
e. An acquired immunodeficiency syndrome-defining opportunistic
infection within 6 months of the start of screening.
f. Human immunodeficiency virus load ≥ 400 copies/mL.
17.Active or symptomatic viral hepatitis or chronic liver disease;
encephalopathy, ascites or bleeding disorders secondary to hepatic
dysfunction.
18.Criterion modified per Amendment 2.
18.1. Moderate or severe hepatic impairment (Class B and C per Child-
Pugh classification system (Appendix 9). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Radiographic progression-free survival (rPFS)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| While on study treatment, radiographic imaging will be performed every 8 weeks for the first 6 months and every 16 weeks thereafter |
|
| E.5.2 | Secondary end point(s) |
* OS
* Time to symptomatic progression
* Time to subsequent therapy
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Assessments of the secondary endpoints are variable but carried out on a regular basis throughout study as described in the endpoint requirements |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 150 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Malaysia |
| New Zealand |
| Ukraine |
| Taiwan |
| Australia |
| Belarus |
| Brazil |
| Canada |
| China |
| Israel |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| South Africa |
| Thailand |
| Turkey |
| United Kingdom |
| United States |
| Belgium |
| Bulgaria |
| Czechia |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Spain |
| Sweden |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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