PARP inhibitors in ovarian cancer: Current status and future promise

Highlights

• Poly(ADP-ribose) polymerase (PARP) inhibitors are one of the most exciting new classes of targeted agents for ovarian cancer treatment.

• PARP inhibitors have demonstrated single-agent activity in BRCA-related ovarian cancer and sporadic high grade serous ovarian cancer.

• Phase III PARP inhibitor studies have been launched for newly diagnosed germline BRCA cancers and platinum sensitive recurrent ovarian cancer.

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.

Introduction

Poly(ADP-ribose) polymerase (PARP) inhibitors are one of the most exciting new classes of targeted agents currently in clinical trials for ovarian cancer [1], [2]. From the original in vitro observation that PARP inhibitor have anti-cancer activity in BRCA-deficient cells to the demonstration that these agents have single-agent anti-cancer activity in BRCA-related recurrent ovarian cancer, these agents are poised to ultimately change how patients with BRCA-related ovarian cancer are treated [3], [4], [5]. The PARP inhibitor field was initially slowed with the publication of a negative Phase III study testing iniparib combined with carboplatin and gemcitabine for the treatment of triple negative breast cancer; however, the field has been accelerated by the results of studies of several PARP inhibitors in ovarian cancer demonstrating anti-cancer activity in addition to the in vitro observation that iniparib does not have anti-PARP activity at physiological doses. In addition, PARP inhibitors appear to be well tolerated as well and have mostly myelosuppression and gastrointestinal toxicity. Several phase III FDA registration studies of PARP inhibitors have been initiated in both recurrent and newly diagnosed ovarian cancer that focus on using PARP inhibitors as single-agent maintenance therapy following chemotherapy; overlapping myelosuppressive effects of PARP inhibitor with chemotherapy and demonstration of single-agent activity of PARP inhibitor have led to this strategy. This FDA registration trial design is based on the findings of a randomized phase II study that tested the PARP inhibitor olaparib versus placebo maintenance in women with recurrent platinum-sensitive ovarian cancer [6]. This study specifically focused on women with HGSC, a subtype of ovarian cancer where DNA repair abnormalities are estimated to be present in approximately 50% of cases [7]. In this study, women receiving olaparib had a significant improvement in progression-free survival (PFS) compared to those receiving placebo; this improvement was even more pronounced in women who harbored a BRCA mutation [8]. In this review, we will discuss the clinical development of the current PARP inhibitors, as well as future challenges for this exciting drug class.