A Phase 2 Efficacy and Safety Study of Niraparib in Men with Metastatic Castration-
Resistant Prostate Cancer and DNA-Repair Anomalies

PARPs are enzymes responsible for repair of DNA single-strand breaks (SSBs)
through a process called base excision repair. PARP inhibition leads to an
accumulation of unrepaired SSBs, which result in stalling and collapse of
replication forks and, consequently, to double-stranded breaks (DSBs).
Normally, DSBs are repaired through homologous recombination (HR). If not
repaired, DSBs result in cell death. When tumor cells with DNA repair defects
involving the HR pathway (eg, Breast Cancer genes [BRCA]-1/2) are treated with
a PARP inhibitor, they are unable to efficiently and accurately repair DSBs,
which creates a synthetic lethal condition. In men with metastatic
castration-resistant prostate cancers (mCRPC), tumors with DNA-repair anomalies
account for approximately 20% to 30% of the sporadic cancers.
For many years, the established standard of care for men with mCRPC was
docetaxel chemotherapy. More recently, androgen receptor (AR)-targeted agents
such as abiraterone acetate (ZYTIGA®) and enzalutamide (XTANDI®) have improved
time to progression and survival rates, when indirectly compared to docetaxel.
However, there remains a subset of patients who either do not respond
initially, or become refractory to these treatments. No approved therapeutic
options are available for such patients. Platinum-based chemotherapy has been
tested in a number of clinical studies in molecularly unselected prostate
cancer patients with limited results and significant toxicities.3,5 PARP
inhibition may be a treatment option for mCRPC patients with DNA-repair
anomalies following chemotherapy and AR-targeted agents.

Primary objective:
- To assess the efficacy of niraparib in subjects with measurable mCRPC and who
have either biallelic DNA-repair anomalies in BRCA (BRCA 1 and BRCA 2 or
germline BRCA.
Secondary objectives:
- To assess the efficacy of niraparib in subjects with measurable mCRPC and
DNA-repair anomalies in biallelic non-BRCA (ATM, FANCA, PALB2, CHEK2, BRIP1 or
HDAC1)
- To assess the efficacy of niraparib in subjects with mCRPC and DNA-repair
anomalies by following up CTC (circulating tumor cells)
- To evaluate response outcomes of niraparib in subjects with mCRPC and
DNA-repair anomalies
OS: time from enrollment to death from any cause
- As defined by PCWG3:
* rPFS: time from enrollment to radiographic progression or death from any
cause, whichever occurs first
* Time to radiographic progression
* Time to PSA progression
* Time to symptomatic skeletal event (SSE)
- To evaluate the safety and tolerability of niraparib
- To evaluate duration of tumor response

This is a Phase 2, multicenter, open-label study to assess the efficacy and
safety of once daily dosing of 300 mg niraparib in male subjects over the age
of 18 years with mCRPC and DNA-repair anomalies
- who have progressed on or after taxane-based chemotherapy or discontinued
chemotherapy due to intolerability (Adverse events)
- who have progressed on or after AR-targeted therapy (eg, abiraterone acetate
with prednisone, enzalutamide, apalutamide).
The study will enroll approximately 155 subjects with measurable disease, who
are biomarker positive (100 subjects with DNA-repair anomalies in BRCA1 or
BRCA2 and 55 DNA with DNA-repair anomalies in ATM, FANCA, PALB2, CHEK2, BRIP1,
or HDAC2. In addition, approximately 60 subjects with non-measurable disease
(ie, bone disease only) will be included to evaluate the activity of niraparib
in this population. All subjects will be monitored for safety during the study
period, and up to 30 days after the last dose of study drug. Treatment will
continue until disease progression, unacceptable toxicity, death, or the
sponsor terminates the study.
Efficacy analysis will be evaluated on subjects enrolled after 07 DEC 2017.
The study will consist of 4 phases; a Prescreening Phase for biomarker
evaluation only, a Screening Phase, a Treatment Phase, and a Follow-up Phase.
A Long-term Extension phase will be added under protocol amendment 8:
participants can be treated with niraparib until they no longer derive benefit
from treatment or until further notification on different means of study
treatment.

All patients will receive treatment with Niraparib 300mg/day (3 capsules of
100mg)

The procedures required in the trial are also done in the standard treatment
setting, although certain procedures (eg. blooddraws for pharmacokinetics,
pharmacodynamics and biomarkers as well as the number of CT/MRI and bone scans)
are done more often than in the standard treatment. The trial medication can
lead to side effects. The extra trial procedures and possible side effects
observed until now are considered to be acceptable, taken into account the
expected therapeutic benefit of the trial medication.