PARP inhibitors currently in clinical development

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            A number of pharmaceutical companies have designed PARP inhibitors; however, despite the high interest in this class of compounds, development of a number of them has stalled.  Currently, the three main PARP inhibitors under active study are rucaparib, olaparib, and veliparib.  These three compounds will be the focus for the remaining discussion.  This section will review the preclinical evaluations and single agent dose escalation results for each of these compounds.  Subsequent sections will discuss these agents in: 1) breast and ovarian cancer patients with germline BRCA1/2 mutations; and 2) in combination with other treatment modalities.

                Rucaparib (AG-014699) is a potent inhibitor (K_i=1.4 nM) of PARP-1 and PARP-2 with preclinica modeling demonstrating that combining rucaparib with either the alkylating agent temozolomide or the topoisomerase inhibitor irinotecan improved overall clinical efficacy of the cytotoxic agents (54).   As the first PARP inhibitor to be evaluated in human studies, rucaparib was initially only formulated for intravenous use and was tested in combination with temozolomide.  Single-agent testing of the agent occurred only after the combination of it with temozolomide proved too toxic.  As a single agent administered to 38 evaluable BRCA1/2 deficient breast and ovarian cancer patients, a 5% partial response rate (PR) was observed with 26% of participants achieving SD ≥ 4 months with no significant toxicities reported (55).  In order to facilitate continuous dosing schedules, rucaparib recently has been converted to an oral formulation and is being reevaluated in phase I dose escalation (NCT01482715).  This trial is currently ongoing.  Clinical trials of rucaparib in combination with temozolomide are discussed in the section below.

                Olaparib (AZD-2281) is a potent, orally administered PARP inhibitor (K_i=5 nM and 1 nM for PARP-1 and 2 respectively) with preclinical evidence of in vitro and in vivo activity in HR-deficient cell lines and in combination with alkylating agents (56).  In phase I dose escalation, the maximally tolerated dose was 400 mg twice a day, with responses only seen in BRCA1/2 deficient tumors.  In a cohort separate from the dose escalation, 19 BRCA deficient tumors were evaluated; in this cohort, 47% obtained a PR and 63% experienced clinical benefit (defined as either PR or SD ≥ 4 months), suggesting potent single-agent activity in this population (57). 

                Veliparib (ABT-888) is an orally administered PARP inhibitor with highly potent inhibitory activity against both PARP-1 and PARP-2 (K_i=5.2 nM and 2.9 nM for PARP-1 and 2 respectively).  Preclinical models have suggested that veliparib increased the activity of temozolomide, cisplatin, carboplatin and cyclophosphamide.   In addition, veliparib appeared to increase the cytotoxic efficacy of radiation therapy (58, 59).  In phase 0 testing, veliparib was well tolerated with the dose of 50 mg twice a day; in tumor biopsies, PARP activity was inhibited by 95% at this dose (60).

                Initially thought to be a PARP inhibitor, early phase clinical trials of iniparib (BSI-201) in estrogen receptor, progesterone receptor and HER2 negative breast cancers, known as the triple-negative phenotype (TNBC), suggested that this agent was beneficial when administered in combination with carboplatin and gemcitabine (61, 62).  Based on these results, a randomized phase III trial was initiated; however, the trial did not meet the pre-specified criteria for significance in terms of progression free survival (PFS) and overall survival (OS).  Further work into the mechanisms of iniparib has indicated that the drug is not a functional PARP inhibitor but instead works synergistically with chemotherapy to increase DNA damage (63).  For this reason, iniparib will not be considered further in this review.