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PARP inhibitors in ovarian cancer: current status and future promise

Joyce F Liu¹, Panagiotis A Konstantinopoulos¹, Ursula A Matulonis¹

¹Gynecologic Oncology Program, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215, USA.

Gynecologic Oncology

|March 11, 2014

Abstract:

Clinical investigation of poly(ADP-ribose) polymerase (PARP) inhibitors for ovarian cancer treatment has rapidly evolved from observations of single-agent in vitro activity of these agents in BRCA-deficient cancer cells in 2005 to the initiation of multiple phase III studies in 2013. With clinical trial design and treatment of ovarian cancer increasingly based on histological and molecular characteristics, PARP inhibitors are on the horizon of becoming the first biologic agents to be used to treat ovarian cancer based upon pre-selection characteristics of the patient's cancer. PARP inhibitors are most active in ovarian cancers that have defects or aberrations in DNA repair; use of these agents has been of particular interest in high grade serous cancers (HGSC), where studies have shown that ~50% of HGSC have abnormalities of DNA repair through BRCA germline and somatic mutation, post-translational changes of BRCA, and abnormalities of other DNA repair molecules. In addition, as aberrant DNA pathways in other histological subtypes of ovarian cancer are identified, and through the combination of PARP inhibitors with other biologic agents, the pool of eligible patients who may benefit from PARP inhibitors will likely expand. Pending review by the Food and Drug Administration (FDA) and the outcome of confirmatory phase III studies, PARP inhibitors could become the first FDA-approved biologic agent for ovarian cancer and also the first new FDA-approval in ovarian cancer since carboplatin and gemcitabine were approved for platinum sensitive ovarian cancer in 2006. This review discusses the PARP inhibitors that are currently in testing for ovarian cancer treatment and the future of this class of anti-cancer agents.

Insights

Poly(ADP-ribose) polymerase (PARP) inhibitors show promise for ovarian cancer, particularly in BRCA-mutated tumors. These agents represent a new class of targeted therapy for ovarian cancer, pending FDA approval.

Area of Science:

Oncology
Genetics
Pharmacology

Background:

Clinical investigation of poly(ADP-ribose) polymerase (PARP) inhibitors for ovarian cancer has advanced significantly since 2005.
Treatment strategies for ovarian cancer are increasingly tailored to histological and molecular characteristics.
PARP inhibitors are poised to be the first biologic agents for ovarian cancer based on patient-specific cancer profiles.

Purpose of the Study:

To review the current status and future prospects of PARP inhibitors in ovarian cancer treatment.
To discuss the molecular basis for PARP inhibitor activity in ovarian cancer.
To explore the expanding role of PARP inhibitors in ovarian cancer therapy.

Main Methods:

Review of clinical investigations and phase III studies of PARP inhibitors in ovarian cancer.
Analysis of molecular characteristics, including DNA repair defects and BRCA mutations, in high-grade serous ovarian cancer (HGSC).
Discussion of potential combinations of PARP inhibitors with other biologic agents.

Main Results:

PARP inhibitors demonstrate significant activity in ovarian cancers with DNA repair defects, notably in HGSC where ~50% exhibit BRCA-related abnormalities.
The efficacy of PARP inhibitors is linked to specific molecular aberrations in DNA repair pathways.
The pool of eligible patients may expand as other histological subtypes and combination therapies are explored.

Conclusions:

PARP inhibitors are a promising targeted therapy for ovarian cancer, especially in patients with DNA repair deficiencies.
These agents could represent the first FDA-approved biologic therapy for ovarian cancer based on pre-selected characteristics.
Further clinical trials and FDA review will determine the future role of PARP inhibitors in ovarian cancer treatment.

Read full analysis

Keywords:

BRCA Ovarian cancer PARP inhibitors

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