Fong
et al have has first demonstrated the activity of single agent PARP
inhibitor olaparib in BRCA-deficient advanced ovarian, breast and
prostate cancers [
43], with greater activity observed in platinum sensitive ovarian cancer patients [
44].
Response rates of 30% have been reported in a subsequent phase II
studies conducted in refractory advanced BRCA-mutant ovarian cancer [
45],
suggesting BRCA1-2 mutations as potential predictive biomarkers for
clinical use. However another phase II study including both BRCA mutant
and wild type patients with breast cancer and HGSOC showed encouraging
activity also in the cohort of wild type, platinum-sensitive HGSOC
patients [
46],
likely due to the acquired defects of HR genes responsible for
“BRCA-like phenotype”, which conferred the same sensitivity to both
platinum-chemotherapy and PARP inhibition. All such findings have led to
the design of a randomized phase III, placebo controlled trial, of
olaparib as single agent maintenance therapy in patients with recurrent
HGSOC who responded to prior platinum-based chemotherapy, showing a
significant improvement of
3.6 months progression free survival (PFS) in
the overall population (HR: 0.35,
p < 0·001), with the greatest increment of 6.9 months PFS (HR 0.18,
p < 0.0001) occurring in the subgroup of patients with BRCA mutations [
47].
The
updated analysis of the study 19 has recently shown a significant
overall survival benefit limited to the BRCA mutant patients (34.9
vs 30.2 months; HR: 0.62,
p = 0.025), which was not extended to the wild type population (HR 0.83,
p
= 0.37). As expected adverse events like fatigue, anemia, nausea and
vomiting were significantly higher with olaparib than placebo [
48].
On the basis of such positive results olaparib was the first
PARP-inhibitor receiving the approval by the European Medical Agency
(EMA) at doses of 400 mg twice daily as maintenance therapy for
platinum-sensitive patients with advanced HGSOC, fallopian tube, or
primary peritoneal cancer, harboring BRCA-mutations.
A companion
diagnostic test has been also approved by FDA to identify mutations in
BRCA1/2 genes using DNA obtained from a blood sample. Along with
olaparib, several other PARP inhibitors, including veliparib, rucaparib
and niraparib have shown encouraging activity and acceptable safety
profile in early phase I-II studies. In particular the phase II
randomized ARIAL 2 study of
rucaparib has shown an objective response
rate (ORR) of 80% and median PFS of
12.8 months in BRCA-mutant platinum
sensitive patients with recurrent ovarian cancer and ORR 39% with and
median PFS of 7.2 months in BRCA wild type patients with a BRCA-like
signature, compared to ORR of 13% and median PFS of 5 months in
biomarker negative patients.
Rucaparib was associated with a manageable
safety profile, including nausea, asthenia/fatigue and ALT/AST
elevations among the most common treatment-related AEs [
49,
50].
These impressive results led to the recent Breakthrough Therapy
designation status of rucaparib by the FDA for the treatment of ovarian
cancer, while the ARIEL3 randomized study is currently recruiting
patients.
Veliparib has recently shown a significant activity and
tolerable safety profile as single agent in a phase II single arm trial
including ovarian cancer patients carrying a germline BRCA1-2 mutation
who progressed to prior chemotherapy regimens, reporting ORR of 35% and
20% in platinum-sensitive and platinum-resistant patients, respectively [
51].
A phase 3 trial is currently ongoing in order to further elucidate the
potential of this drug in such setting. Niraparib 300 mg/day has shown a
good safety profile and a promising activity with ORR 40% in
pre-treated ovarian cancer patients with BRCA 1-2 mutations [
52].
The phase III randomized ENGOT-OV16/NOVA trial investigated the PARP
inhibitor niraparib as single agent maintenance therapy in patients with
recurrent, platinum sensitive HGSOC, stratified by BRCA-mutation
status. The study has met its primary end-point showing a significant
PFS improvement both in BRCA-mutant (HR: 0.27;
p < 0.001) and in BRCA-wild type (HR: 0.45;
p
< 0.0001) populations. A further analysis of BRCA-wild type patients
identified the subgroup of HRD-positive patients who receive more
benefit (HR: 0.38;
p < 0.001) compared to HRD-negative patients (HR: 0.58;
p < 0.0226) [
53].
The large benefit observed in the overall population included in the
NOVA study could led to a fast approval of niraparib in the treatment of
platinum sensitive recurrent ovarian cancer, regardless of BRCA-status.
An alternative approach has been investigated by another phase II
randomized trial comparing olaparib plus chemotherapy (paclitaxel and
carboplatin), followed by olaparib single agent maintenance
versus
chemotherapy alone in platinum-sensitive recurrent HGSOC patients. The
results of such trial showed that combining olaparib 200 mg twice daily
for 10 days of each cycle with lower dose of carboplatin (AUC 4) plus
paclitaxel, followed by olaparib 400 mg twice daily as maintenance
treatment is an effective and tolerable option leading to a significant
2.6-month PFS advantage (HR 0.51,
p = 0.0012), with the greatest clinical benefit in BRCA-mutated patients (HR: 0.21,
p = 0.0015) [
54]. The addition of
veliparib to cyclophosphamide didn’t improve RR and PFS in patients with recurrent HGSOC [
55], while another phase II randomized study comparing
veliparib plus temozolomide vs
PLD in the same setting of patients has just completed recruitment
(NCT01113957, https://clinicaltrials.gov/ ). A very promising strategy
emerged from the phase II randomized trial by Liu et al. which showed a
further PFS benefit from adding the anti-angiogenic agent
cediranib to
olaparib for platinum-sensitive, recurrent, HGSOC, fallopian tube, or
primary peritoneal
cancer (median PFS 17.7
vs 9 months; (HR: 0.42;
p = 0·005) [
56],
warranting investigation in a phase III ongoing trial. Similarly a
phase I-II study is currently comparing tolerability and efficacy of
niraparib alone
versus niraparib-bevacizumab combination
versus sequential bevacizumab and niraparib in platinum sensitive relapsed ovarian cancer [
57],
while the PAOLA1 trial is currently investigating first-line
chemotherapy with bevacizumab plus olaparib or placebo as maintenance
treatment. Finally the combination of olaparib and PD-L1 checkpoint
inhibitor
Durvalumab has shown promising durable long-term responses and
a tolerable safety profile in pre-treated ovarian cancer and triple
negative breast cancer (TNBC) patients [
58].....
