This is a 2-arm, prospective, randomized (2:1 ratio), open-label, multi-centre, phase II study conducted in patients affected by unresectable, locally advanced or metastatic urothelial cancer receiving niraparib plus best supportive care versus best supportive care as maintenance therapy after a first-line platinum-based chemotherapy.

The primary objective of the trial is to evaluate the efficacy of niraparib plus Best Supportive Care (BSC) vs. BSC alone, as maintenance treatment, in terms of prolongation of progression-free survival (PFS), in patients with locally advanced or metastatic urothelial cancer that obtained disease control (objective response or stable disease) with first-line platinum-based chemotherapy.

This is a 2-arm, prospective, randomized (2:1 ratio), open-label, multi-centre, phase II study conducted in patients affected by unresectable, locally advanced or metastatic urothelial cancer receiving niraparib plus best supportive care versus best supportive care as maintenance therapy after a first-line platinum-based chemotherapy.

The primary objective of the trial is to evaluate the efficacy of niraparib plus Best Supportive Care (BSC) vs. BSC alone, as maintenance treatment, in terms of prolongation of progression-free survival (PFS), in patients with locally advanced or metastatic urothelial cancer that obtained disease control (objective response or stable disease) with first-line platinum-based chemotherapy.

Poly-adenosine diphosphate ribose polymerase (PARP) inhibitors sensitivity is based on the presence of truncating and missense mutations in genes associated with the homologous recombination pathways. In The Cancer Genome Atlas dataset approximately 34% of bladder urothelial carcinoma harbored these mutations. Furthermore, in this study we plan to select a population potentially sensible to niraparib, by enrolling patients responding to platinum, indeed we know that there is a cross-sensitivity and a cross-resistance between platinum drugs and PARP inhibitors in urothelial carcinoma.

PFS is commonly adopted as primary endpoint in randomized phase II trials. Randomized design for phase II trials has been increasingly adopted in recent years, to allow a formal comparison between experimental and standard treatment. This should lead to a better interpretation of the results obtained with the experimental treatment, that are in most cases difficult to interpret in the absence of controls.

The sample size of the study is calculated with "relaxed" statistical criteria. The study design will verify if the experimental treatment (Niraparib) is promising enough to warrant a phase 3 trial for efficacy compared to observation.

A total of 65 PFS events are needed to provide 80% power to detect an hazard ratio (HR) of 0.57 (1.75), corresponding to a median increase in progression-free survival from 4 to 7 months, with one-tailed alpha 0.1.

With an accrual duration of 24 months, and additional 6 months of follow up after the completion of recruitment, 77 patient need to be randomized (26 assigned to control arm and 51 assigned to experimental arm) to obtain the 65 events needed.

Sample size of the phase II trial is too small to plan a formal analysis of interaction of treatment efficacy with type of response at first line treatment (i.e. objective response vs. stable disease). However, type of response to first line treatment will be among stratification factor for randomization, so the 2 treatment groups will be balanced. Exploratory subgroup analysis of treatment efficacy in patient who have obtained objective response with first line and in patients who have obtained stable disease with first line will be performed.

Inclusion Criteria:

1. Participant must have histologically/cytologically confirmed, unresectable locally advanced or metastatic transitional cell carcinoma of the urothelium (transitional cell carcinoma either pure or mixed histology)

2. Measurable disease (per RECIST v1.1) prior to the start of first-line chemotherapy

3. Prior first-line chemotherapy must have consisted of at least 4 cycles and no more than 6 cycles of platinum containing regimen (cisplatin or carboplatin)

4. No evidence of progressive disease following completion of first-line chemotherapy (i.e., ongoing complete response (CR), partial response (PR), or stable disease (SD) per RECIST v1.1 guidelines )

5. Patients must be enrolled within 4 weeks of scans demonstrating stable disease/partial-complete response and no more than 6 weeks after receiving the last standard chemotherapy dose

6. Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

7. Participant must be ≥ 18 years of age

8. Participant must have adequate bone marrow and organ function, defined as follows:

   • Absolute neutrophil count ≥ 1,500/µL
   • Platelets ≥ 100,000/µL
   • Hemoglobin ≥ 9 g/dL
   • Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault equation
   • Total bilirubin ≤ 1.5 x ULN (≤2.0 in patients with known Gilberts syndrome) OR direct bilirubin ≤ 1 x ULN
   • Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x ULN unless liver metastases are present, in which case they must be ≤ 5 x ULN

9. Participant receiving corticosteroids is eligible if their dose is stable for least 4 weeks prior to initiating protocol therapy.

10. Participant must agree to not donate blood during the study or for 90 days after the last dose of study treatment.

11. Female participant has a negative urine or serum pregnancy test within 7 days prior to taking study treatment if of childbearing potential and agrees to abstain from activities that could result in pregnancy from screening through 180 days after the last dose of study treatment, or is of non-childbearing potential. Non-childbearing potential is defined as follows (by other than medical reasons):

    • ≥45 years of age and has not had menses for >1 year
    • Patients who have been amenorrhoeic for <2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation
    • Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure, otherwise the patient must be willing to use 2 adequate barrier methods throughout the study, starting with the screening visit through 180 days after the last dose of study treatment.

    Note: Abstinence is acceptable if this is the established and preferred contraception for the patient.

12. Participant must agree to not breastfeed during the study or for 180 days after the last dose of study treatment.

13. Male participant agrees to use an adequate method of contraception starting with the first dose of study treatment through 180 days after the last dose of study treatment. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient.

14. Participant must be able to understand the study procedures and agree to participate in the study by providing written informed consent

15. Blood sample availability, to determine germline BRCA mutation status

16. Archived tumor tissue sample availability to determine homologous recombination deficiency (HRD) status

Exclusion Criteria:

1. Participant must not be simultaneously enrolled in any interventional clinical trial
2. Participant must not have had major surgery ≤ 3 weeks prior to initiating protocol therapy and participant must have recovered from any surgical effects.
3. Participant must not have received investigational therapy ≤ 4 weeks, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is shorter, prior initiating protocol therapy.
4. Participant must not have received radiation therapy encompassing >20% of the bone marrow within 2 weeks; or any radiation therapy within 1 week prior to Day 1 of protocol therapy.
5. Participant must not have a known hypersensitivity to niraparib components or excipients.
6. Participant must not have been treated previously with a known PARP inhibitor agent
7. Participant must not have received a transfusion (platelets or red blood cells) ≤ 4 weeks prior to initiating protocol therapy.
8. Participant must not have received colony stimulating factors (e.g., granulocyte colony-stimulating factor, granulocyte macrophage colony stimulating factor, or recombinant erythropoietin) within 4 weeks prior initiating protocol therapy.
9. Participant must not have experienced any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior chemotherapy that persisted > 4 weeks.
10. Participant must not have any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)
11. Participant must not have a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent
12. Participant must not have a diagnosis of any other malignancy within 2 years prior to randomization, except for adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the breast or of the cervix, low grade prostate cancer on surveillance without any plans for treatment intervention, or prostate cancer that has been adequately treated with prostatectomy or radiotherapy and currently with no evidence of disease or symptoms.
13. Participant must not have history of or known spinal cord compression, or carcinomatous meningitis, or evidence of symptomatic brain or leptomeningeal disease on screening CT or MRI scan. However treated, stable and asymptomatic brain metastases are allowed.