A feasibility study of niraparib for advanced, BRCA1-like, HER2-negative breast cancer patients: the ABC study

Evidence from preclinical and clinical studies has emerged that breast cancer
cells deficient in homologous recombination to repair DNA double strand breaks
(DSBs), as in BRCA1/2-mutated cells, offers a target for DNA DSB-inducing
regimens, such as alkylating agents, platinum compounds or poly(ADP)ribose
polymerase (PARP) inhibitors. Recently, a putative companion diagnostic has
been derived from the characteristic DNA copy number aberrations present in
BRCA1-mutated breast cancers. This test has been coined the *BRCA1-like test*.
BRCA1-like tumors comprise ±7.5% of all breast cancers5-7. BRCA1-like tumors
can be divided into three groups: ± 25% have a BRCA1-mutation, ±35% have a
BRCA1 promoter hypermethylation causing silencing of the BRCA1 gene, and for ±
40% the underlying molecular aberration is unknown. Circa 80-90% of BRCA1-like
tumors are hormone receptor-negative, and HER2 negative (so-called *triple-
negative*) breast cancers9. Within the triple-negative breast cancer subgroup,
depending on the median age of the case mix, ± 50% of cases are BRCA1-like,
which percentage is inversely correlated with median age.
The BRCA1-like test can be read out from both DNA (formalin-fixed,
paraffin-embedded (FFPE) tumor material)10 or RNA (fresh frozen (FF) tumor
material)11. The test is robust, reproducible and has shown clinical validity
and utility as a companion diagnostic in selecting high-risk breast cancer
patients for DNA DSB-inducing regimens, notably intensified alkylating
chemotherapy (DNA-based test) and the combination of carboplatin/veliparib
added to standard adjuvant chemotherapy (RNA- based test)12. Since the
RNA-based BRCAness classifier has been shown to predict benefit from
carboplatin/veliparib in the ISPy-2 study, we propose to use this classifier to
select patients that are likely to benefit from niraparib.
Since no data exist on progression-free survival (PFS) of BRCA1-like metastatic
breast cancer patients, we can only use the proxy of triple-negative breast
cancers. Data from recently published studies suggests that the median PFS
after first line treatment is ~ 6 months, and after second line treatment this
is ~ 3 months. Recently, two studies reported on single agent olaparib activity
in advanced BRCA-mutated and TNBC patients who had received a median of three
prior chemotherapy regimens. Median PFS in the BRCA-mutated patients was 4-6
months17, and in the TNBC patients it was ± 2 months18. Unpublished preliminary
data in PDX models suggest that besides BRCA-mutated breast cancers, also
non-BRCA-mutated, BRCA1-like breast cancers may derive benefit from single
agent PARP-inhibitors. In the currently proposed study we would like to
investigate whether development of single agent PARP-inhibitors for incurable
BRCA1-like breast cancer patients deserves to be further studied.
Treatment of patients with locally recurrent BRCA1-like, HER2-negative breast
cancer that cannot be treated with curative intent by local treatment (surgery,
radiotherapy +/- hyperthermia) or patients with metastatic BRCA1-like,
HER2-negative breast cancer that have received a maximum of one prior line of
treatment for incurable disease

To establish whether niraparib single agent treatment in advanced BRCA1-like,
HER2 negative breast cancer patients deserves to be further studied

Single arm, open-label, multicenter, phase II study with a Simon*s two-stage
design

Burden and risks
1. Mandatory tumor biopsy before start of treatment.
2. Optional: 2 extra tumor samples (taken for the same location as mandatory
tumor biopsy)
3. Additional blood samples
4. At start and every 2 cycles CT-chest/abdomen until progression
5. Extra hospital visits, specifically before start and during first treatment
cycle.
6. Optional: tumor biopsy at Niraparib resistance
7. Optional: additional blood samples for ctDNA, NGS en research into immune
modulation by PARP-inhibitors