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abstract
Published online before print March 28, 2016
High-grade serous ovarian cancer is
characterized by genomic instability, with one half of all tumors
displaying defects in
the important DNA repair pathway of homologous
recombination. Given the action of poly(ADP-ribose) polymerase (PARP)
inhibitors
in targeting tumors with deficiencies in this
repair pathway by loss of BRCA1/2, ovarian tumors could be an
attractive population for clinical application of this therapy. PARP
inhibitors have moved into
clinical practice in the past few years, with
approval from the Food and Drug Administration (FDA) and European
Medicines
Agency (EMA) within the past 2 years. The U.S.
FDA approval of olaparib applies to fourth line treatment in germline BRCA-mutant ovarian cancer, and European EMA approval to olaparib maintenance in both germline and somatic BRCA-mutant
platinum-sensitive ovarian cancer. In order to widen the ovarian cancer
patient population that would benefit from
PARP inhibitors, predictive biomarkers based on a
clear understanding of the mechanism of action are required.
Additionally,
a better understanding of the toxicity profile
is needed if PARP inhibitors are to be used in the curative, rather than
the
palliative, setting.
We reviewed the development
of PARP inhibitors in phase I–III clinical trials, including
combination
trials of PARP inhibitors and
chemotherapy/antiangiogenics, the approval for these agents, the
mechanisms of resistance, and
the outstanding issues, including the
development of biomarkers and the rate of long-term hematologic
toxicities with these
agents.
Implications for Practice:
The poly(ADP-ribose) polymerase (PARP)
inhibitor olaparib has recently received approval from the Food and Drug
Administration
(FDA) and European Medicines Agency (EMA), with a
second agent (rucaparib) likely to be approved in the near future.
However,
the patient population with potential benefit
from PARP inhibitors is likely wider than that of germline BRCA
mutation-associated disease, and biomarkers are in development to
enable the selection of patients with the potential for
clinical benefit from these agents. Questions
remain regarding the toxicities of PARP inhibitors, limiting the use of
these
agents in the prophylactic or adjuvant setting
until more information is available. The indications for olaparib as
indicated
by the FDA and EMA are reviewed.
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