This is a Multicenter, Open-label, Phase II Clinical Trial to Evaluate the Efficacy and
Safety of Niraparib plus Aromatase Inhibitors for Hormone Receptor (HR)-positive/Human
Epidermal Growth Factor Receptor 2 (HER2)-negative Metastatic Breast Cancers with either
Germline BRCA-mutated or Germinal BRCA-wild-type and Homologous Recombination Deficiency
The main objetive is to assess the efficacy -as determined by the clinical benefit rate
(CBR)- of niraparib in combination with AIs in unresectable locally advanced or metastatic
HR-positive/HER2-negative breast cancer patients harboring either gBRCAms or gBRCAwt and HRD.
Upon meeting all selection criteria, patients enrolled in the study will receive the
combination of niraparib either 300 mg or 200 mg orally (according to baseline criteria
described in Table 4), once daily, flat- fixed, continuously in 28-day cycles and AI that
must be identical to the last AI-containing regimen.
A total of 23 patients will be recruited as follows:
- Stage I: N=6 patients in the cohort A;
- Stage II: N=8 patients in the cohort A; N=9 patients in the exploratory cohort B
The total duration of the study period is 36 months follow until 5 years of follow up.
- 1. Patients have been informed about the nature of study, including the exploratory
sub-study and has agreed to participate and signed the informed consent prior to
participation in any study- related activities.
- 2. Male or female patients ≥ 18 years of age.
- 3. Eastern Cooperative Oncology Group (ECOG) performance status must be 0 or 1 which
the Investigator believes is stable at the time of screening.
- 4. Life expectancy ≥16 weeks.
- 5. Patients have a histologically and/or cytologically confirmed diagnosis of breast
- 6. Patients have radiologic evidence of inoperable locally recurrent or metastatic
breast cancer (MBC) that are not candidates for curative intent.
- 7. Patients have human epidermal growth factor receptor 2 (HER2)- negative breast
cancer (based on most recently analyzed biopsy) defined as a negative in situ
hybridization (ISH) test or an immunohistochemistry (IHC) status of 0, 1+, or 2+ (if
IHC 2+, a negative ISH test is required) by local laboratory testing.
- 8. Patients have hormone receptor (HR)-positive breast cancer (based on most recently
analyzed biopsy) defined as estrogen receptor (ER) and/or progesterone receptor (PgR)
with ≥10% of tumor cells positive for ER and/or PgR by IHC irrespective of staining
- 9. [Cohort A]: Patients with documented germinal mutation in BRCA1 or BRCA2 genes that
is predicted to be deleterious or suspected deleterious (known or predicted to be
detrimental/lead to loss of function).
- 10. [Exploratory cohort B]: Patients with either germinal BRCA1/2 wild-type (gBRCAwt)
or gBRCAms that are considered to be non- detrimental and homologous recombination
deficiency (HRD) based on the HRDetect predictor test.
- 11. [Exploratory cohort B]: Willingness and ability to provide additional six
formalin-fixed paraffin-embedded (FFPE) tissue slides from the most recent tumor
tissue since last progression (from either metastasis or primary tumor) to centrally
perform the RAD51 assay.
- 12. At least one and up to two prior lines of endocrine therapy (aromatase inhibitors
[AIs] or fulvestrant) for treatment of locally recurrent and/or metastatic disease
(except for patients progressing in the neoadjuvant or adjuvant setting).
- 13. Confirmed disease progression while in the last AI-containing regimen (not
necessarily in the treatment line immediately prior to study entry) with secondary
endocrine resistance criteria.
- 14. Patients may have progressed on no more than one chemotherapy regimens in the
- 15. The following will not be counted as a prior line of cytotoxic chemotherapy:
- Prior hormonal therapy and non-hormonal targeted therapy.
- Targeted and biologic therapies.
- The patient can receive a stable dose of bisphosphonates or denosumab for bone
metastases, before and during the study as long as this was started at least 5
days prior to study treatment.
- 16. Prior carboplatin- or other platinum compound-based therapy is allowed if have
been administered in one of the following settings:
- Disease-free interval > 12 months from date of completion of neoadjuvant or
- As potentially curative treatment for a prior non-breast cancer with no evidence
of disease for ≥ 5 years.
- 17. Patients must have evaluable or measurable disease according to Response
Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1. Patient with
bone-only metastases are eligible.
- 18. Willingness and ability to provide the most recent tumor biopsy since last
progression from either metastatic or primary tissues both at the time of the
inclusion and at disease progression or study termination in order to perform
- 19. Patients must agree to provide blood samples at the time of study inclusion, every
three cycles of treatment, and upon disease progression or study termination in order
to perform exploratory studies.
- 20. Adequate hematologic and organ function within 28 days before the first study
treatment on Cycle 1 Day 1.
- 21. Female patients of childbearing potential must have a negative serum pregnancy
test within 7 days prior to study treatment and must agree to abstain from activities
that could result in pregnancy from screening through 180 days after the last dose of
- 22. Female patients must agree not to breastfeed during the study and for 180 days
after the last dose of study treatment.
- 23. Male patients whose partners are women of childbearing potential must use a condom
during niraparib therapy and for 90 days after receiving the last dose of niraparib.
- 1. HER2-positive disease based on local laboratory results (performed by IHC/in situ
hybridization test) or unknown HER2 status.
- 2. Patients that are candidates for a local treatment with a radical intention.
- 3. Patients that have previously received any PARP inhibitor (PARPi), including
niraparib, in metastatic setting.
- 4. Patients must not be simultaneously enrolled in any interventional clinical trial
and 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.
- 5. Patients who have had radiation therapy encompassing >20% of the bone marrow within
2 weeks prior to start of treatment, excepting for palliative radiation therapy to a
small field >1 week prior to Day 1 of study.
- 6. Patients with visceral crisis who require chemotherapy.
- 7. Patients must not have a known hypersensitivity to niraparib components or
- 8. Patients must not have received a transfusion (platelets or red blood cells) ≤ 4
weeks prior to initiating protocol therapy.
- 9. Patients must not have received colony-stimulating factors (e.g., Granulocyte
colony-stimulating factor [G-CSF], granulocyte macrophage colony-stimulating factor,
or recombinant erythropoietin) within 4 weeks prior initiating protocol therapy.
- 10. Patients have had any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia
due to prior chemotherapy in adjuvant setting or cyclin-dependent kinases (CDK)4/6
inhibitors that persisted > 4 weeks and was related to the most recent treatment.
- 11. Patients must not have any known history of Myelodysplastic syndrome (MDS) or
Acute myeloid leukemia (AML).
12. Patients must not have a serious, uncontrolled medical disorder, nonmalignant
systemic disease, or active, uncontrolled infection.
- 13. Patients must not have had diagnosis, detection, or treatment of another type of
cancer ≤ 2 years prior to initiating protocol therapy.
- 14. Patients with symptomatic uncontrolled brain metastases or leptomeningeal
- 15. Previous allogenic bone marrow transplant or double umbilical cord blood
- 16. Patients who are unable to swallow orally administered medication.
- 17. Patients with gastrointestinal disorders likely to interfere with absorption of
the study medication.
- 18. Chronic daily treatment with corticosteroids with a dose of ≥ 10 mg/day
methylprednisolone equivalent (excluding inhaled steroids), except for prophylaxis
- 19. Female patients who are pregnant or breastfeeding, or adults of reproductive
potential who are not using effective birth control methods.