A Review of PARP Inhibitors in Clinical Development

JHOP - March 2012, VOL 2 NO 1 - Drug Profiles/Updates
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The development of poly (ADP-ribose) polymerase (PARP) inhibitors has expanded the potential for targeting DNA damage in cancer cells. The efficacy of PARP inhibitors in cancer therapy is the subject of an increasing number of clinical trials in a variety of tumor types, including and beyond the expected BRCA mutation malignancies. The established mechanism of action of PARP inhibitors is an important addition to the field of rationally designed drug development through novel trial design, as well as to the development of biomarker investigation.

Table 1
PARP Inhibitors in Development
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There are currently at least 9 PARP inhibitors in clinical development (Table 1). In this review article we describe the evolving role of PARP inhibition in the landscape of personalized therapy, focusing on the 3 PARP inhibitors that are furthest in clinical development.

The Rationale for PARP Inhibition
The accumulation of DNA damage is central to carcinogenesis.1 The mechanisms for repairing single-strand DNA breaks include the base excision repair pathway, in which the PARP family plays a key role.2,3 The most abundant of this group of enzymes is PARP-1; its inhibition leads to double-strand breaks at the replication forks, in the absence of homologous repair.4

The PARP enzymes function through the transfer of ADP-ribose moieties from intracellular nicotin­amide adenine dinucleotide, which leads to the creation of ADP-ribose polymers on the PARP protein and surrounding histones.5 It is believed that these negatively charged ADP-ribose polymers then attract DNA repair proteins, such as XRCC1.6

The products of the tumor-suppressor genes BRCA1 and BRCA2 are integral to homology-directed repair, and a deficiency in these genes leads to disordered DNA damage repair and subsequent carcinogenesis.7-9 Based on the premise that in BRCA mutation cells the base excision repair pathway becomes essential to viability, BRCA-deficient cells have been shown to be exceptionally sensitive to PARP inhibition.10,11

In vitro data in support of PARP inhibition in BRCA mutation cells demonstrated up to 1000-fold increased sensitivity compared with wild-type cells. Furthermore, the selectivity of PARP inhibition was demonstrated through the absence of cytotoxicity in heterozygotic cells, which are capable of repairing double-strand breaks.10 The notion of inducing synthetic lethality through the inhibition of the base excision repair and homologous recombination pathways provided the basis for clinical evaluation of PARP inhibition in tumors known to have BRCA mutations.

Some sporadic tumors also appear to be phenotypically similar to BRCA1 or BRCA2 mutation tumors, without actually bearing germ-line mutations in either the BRCA1 or the BRCA2 gene, a phenomenon that has been described as “BRCAness.”12

The phenotypic likeness between germ-line BRCA1 mutation breast cancers and the basal epithelial subtype of breast cancer (ie, estrogen receptors-negative, progesterone receptors-negative, or HER2-negative, also known as “triple-negative”) has been noted and suggest a common sensitivity to PARP inhibition, a concept that led to clinical trials of PARP inhibition in patients with triple-negative breast cancer.13,14

Although the disruption of homologous recombination through BRCA deficiency comprised a significant fraction of the initial research into the efficacy of PARP inhibition, there is increasing evidence that deficiencies in other proteins involved in homologous repair, such as ATM, CHK2, and FANCF, also impart sensitivity to PARP inhibitors.15 A depletion of these homologous repair proteins is found in a variety of cancers, including chronic lymphocytic leukemia; mantle-cell lymphoma; lung, cervical, and oral cancers; and others.16-20

The possibility that chemotherapy or radiation resistance could be overcome with concomitant PARP inhibition is also a subject of ongoing investigation.21 The cytotoxic effects of chemotherapy and radiation result in PARP-1 activation as a response to DNA damage; hence, PARP inhibitors can potentiate the cellular toxicity induced by DNA-targeted therapies.22-25

Clinical studies of combination therapies were initiated after preclinical findings revealed increased cytotoxicity associated with PARP inhibition in combination with ionizing radiation, platinum agents, temozolomide, and topoisomerase I inhibitors.26-28

Among the PARP inhibitors currently in clinical development, olaparib inhibits both PARP-1 and PARP-2 through binding of the PARP enzymes’ active site, thereby blocking association with the principal substrate, nicotinamide.29 Veliparib has a mechanism of action similar to that of olaparib in its competitive in­hibition of the PARP enzyme.30 In contrast, iniparib appears to irreversibly inhibit the PARP enzyme through a covalent modification.31

This review describes in further detail the available data from clinical studies investigating PARP inhibitors and their potential role in future cancer therapy.

PARP Inhibitors in Clinical Trials
Olaparib
Olaparib is an oral, single-digit nanomolar inhibitor of PARP-1 and PARP-2.29 In vitro studies with olaparib demonstrated inhibition of BRCA1-deficient breast cancer cell lines. In xenograft studies of a genetically engineered mouse model of BRCA1-induced breast cancer, olaparib prolonged survival with no observed toxicity.32 In vivo studies demonstrated that olaparib, in combination with chemotherapeutic agents, confers even greater improvement in survival compared with monotherapy and was associated with acceptable adverse effects.32,33

On the basis of preclinical data, olaparib was evaluated in a phase 1 dose-escalation study involving 60 patients with advanced tumors.34 In this study, eligible patients were initially not required to have BRCA mutations, but provisions in the protocol permitted enrichment of the study population with BRCA mutation carriers. The initial dose was 10 mg once daily for 2 of every 3 weeks. The maximum tolerated dose was established at 400 mg twice daily.34

Responses were observed only in patients with breast, ovarian, or prostate cancer who had BRCA1 or BRCA2 mutations. In all, 63% of patients who were BRCA carriers received clinical benefit from treatment. The toxicities were predominantly grade 1 and 2 and consisted mostly of nausea, fatigue, vomiting, taste alteration, and anorexia.35

To further evaluate this activity, the investigators expanded the study to assess women with BRCA mutation ovarian cancer.35 The majority of patients (39 of 50) received olaparib 200 mg twice daily. The response rate was 40% (95% confidence interval [CI], 26.4%-54.8%), and the median duration of response was 28 weeks. Although the study was not powered to analyze this, the response rate differed in patients with platinum-sensitive disease (61.5%), platinum-resistant disease (41.7%), and platinum-refractory disease (15.4%).35

The drug-related toxicities were predominantly grade 1 or grade 2 and included nausea (32%), fatigue (30%), vomiting (20%), taste alteration (13%), and anorexia (12%).34

Olaparib was further evaluated in two phase 2 studies in patients with BRCA mutations and advanced breast cancer36 or recurrent ovarian cancer.37 In both studies, the dose of olaparib was 400 mg twice daily in cohort 1 and 100 mg twice daily in cohort 2. The rationale for the lower dose was based on pharmacodynamic data from a previous phase 1 trial, in which olaparib at 100 mg twice daily achieved drug concentration sufficient to saturate inhibition of the target in surrogate tissues (peripheral blood mononuclear cells and hair follicles).34

Among 54 patients with breast cancer enrolled in the first study, the overall response rate (ORR) was 42% in cohort 1 and 25% in cohort 2.36 The median progression-free survival (PFS) also seemed to be lower in cohort 2 (3.8 months vs 5.7 months in cohort 1). Patients progressing after platinum chemotherapy rarely had a confirmed response to olaparib.36

Of the 57 patients with ovarian cancer evaluated in the second study, the ORR was 33% in cohort 1 and 13% in cohort 2. Response to olaparib was seen both in patients with platinum-sensitive (38%) or platinum-resistant (30%) disease. The most common nonhematologic toxicities were nausea and fatigue, and anemia was the most common hematologic toxicity.37

Although the response rate was better in patients who received the higher dose (ie, 400 mg twice daily), it is important to note that the 2 cohorts were not randomized; therefore, the results must be interpreted with caution. However, these results do point to the limitations of surrogate markers in determining the “biologically effective dose,” because target inhibition within tumors may differ from inhibition in surrogate tissues. Overall, these 2 trials demonstrate the efficacy and tolerability of olaparib in patients with BRCA1 or BRCA2 mutations.36,37

Table 2
PARP Inhibitors Studied as Single-Agent Therapy
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Phase 1 studies combining olaparib and chemotherapy in the treatment of other solid tumors are ongoing. In one study, the combination of gemcitabine, cisplatin, and olaparib was associated with significant myelosuppression.38 Similarly, in a study of olaparib therapy in combination with dacarbazine, the dose-limiting toxicities were neutropenia and thrombocytopenia. No responses were observed in chemotherapy-naïve patients with melanoma who received the optimally tolerated dose.39 Table 2 lists PARP inhibitors investigated as a single-agent therapy.34,36,37,40-43

Iniparib
Iniparib is an intravenous (IV) PARP-1 and PARP-2 inhibitor. When combined with gemcitabine and carboplatin in an MDA-MB-468(-) triple-negative breast cancer cell line, iniparib increased induction of apoptosis, S-phase and G2/M-cell cycle arrest, and DNA damage coinciding with mitotic arrest.44 Initial dose-escalation studies demonstrated no dose-limiting toxicities at doses ranging from 0.5 to 8 mg/kg.41

Iniparib and its metabolites cross the blood-brain barrier.45 In one case report, iniparib was used by a patient with relapsed triple-negative breast cancer who had developed carcinomatous meningitis.45 The duration of disease-free progression was 5 months, and central nervous system exposure to iniparib was 8% of the total systemic area under the curve (AUC).45

Temozolomide and concurrent radiation therapy are used in the treatment of gliomas; however, resistance to this combination has been demonstrated through DNA repair mechanisms.46 Because iniparib crosses the blood-brain barrier, phase 1 clinical trials are investigating iniparib and temozolomide in patients with malignant glioma.47

In an open-label, randomized, phase 2 study, gem­citabine plus carboplatin, with or without iniparib, was analyzed in 123 women with metastatic triple-negative breast cancer. Gemcitabine 1000 mg/m2 plus carboplatin (in a dose equivalent to an AUC of 2) was given every 21 days on days 1 and 8, with or without IV iniparib 4 mg/kg, on days 1, 4, 8, and 11.47

Among patients who received iniparib, the median PFS was 5.9 months versus 3.6 months in those receiving chemotherapy alone (hazard ratio [HR], 0.59; 95% CI, 0.39-0.09; P = .01), and the median overall survival (OS) was 12.3 months versus 7.7 months, respectively (HR, 0.57; 9% CI, 0.36-0.90; P = .01). Adverse events were similar between the 2 groups.47

Based on these encouraging phase 2 data, a phase 3 trial in patients with triple-negative metastatic breast cancer was launched. The doses and schedule of drugs were identical to the phase 2 trial. A total of 519 patients were enrolled between July 2009 and March 2010, and the final results were reported at the 2011 American Society of Clinical Oncology (ASCO) annual meeting.48

The study failed to meet its coprimary end points of PFS and OS. The median OS in the gemcitabine plus carboplatin alone arm was 11.1 months versus 11.8 months in the iniparib arm (HR, 0.876; P = .284), and the median PFS was 4.1 months versus 5.1 months, respectively (HR, 0.794; P = .027). Grade 3/4 adverse effects were similar in the 2 groups and included neutropenia, anemia, thrombocytopenia, and leukopenia.48

The consent requirement was modified to allow patients to disclose their BRCA mutation status, if known, or to undergo testing as part of the trial, but only few patients consented.

In a subset analysis also discussed at the 2011 ASCO meeting by Dr O’Shaughnessy, the addition of iniparib to chemotherapy in a second- or third-line setting demonstrated a modest benefit in PFS (4.2 vs 2.9 months; P = .031) and OS (10.8 vs 8.1 months; P = .05).48

One possible explanation for the lack of efficacy is that triple-negative breast cancer is a heterogeneous disease with numerous subtypes. A biomarker analysis may help identify a patient population that benefits from the addition of iniparib.

Further analysis of these data is being conducted to determine whether certain populations, such as patients receiving second- or third-line chemotherapy or those with certain molecular subtypes of triple-negative cancer, could benefit from iniparib.

Table 3
PARP Inhibitors Studied in Combination with Chemotherapy
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Currently, numerous phase 1 and 2 trials are under way, the majority involving iniparib in combination with chemotherapy (Table 3).38,39,46,49-62 It is not known which tumor types will be most affected by iniparib. The malignancies currently under investigation include platinum-sensitive and platinum-resistant ovarian cancer, BRCA1 and BRCA2 mutation ovarian cancer, non–small-cell lung cancer, malignant gliomas, and triple-negative breast cancer, in which iniparib is being investigated as neoadjuvant therapy.

Table 3
PARP Inhibitors Studied in Combination with Chemotherapy (Continued)
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Veliparib
Veliparib is an orally available potent inhibitor of PARP-1 and PARP-2.30 Similar to iniparib, veliparib has been demonstrated to cross the blood-brain barrier.30 In tumor-bearing rats that received multiple doses of veliparib (50 mg/kg daily), the maximum concentration of veliparib measured in brain tissue was 0.72 ± 0.12 mcg/g.30 In a study of nonhuman primates that received oral veliparib (5 mg/kg), cerebrospinal fluid penetration measured 57%.63

Veliparib is mainly eliminated through renal secretion; 33% of the drug is metabolized in the liver.64 Cytochrome (CY) P450-2D6 has been identified as the major metabolizer of veliparib. Its allelic variants CYP2D6*10 and CYP2D6*4 are associated with lower metabolic activity.65

In a first-of-its-kind dose-finding phase 0 trial conducted at the National Cancer Institute, veliparib was administered orally in doses of 10 mg, 25 mg, and 50 mg to 13 patients with advanced malignancies. Phase 0 trials were designed in an effort to speed up the development of molecularly targeted agents. They rely on extensive preclinical development and incorporation of real-time pharmacokinetic and pharmacodynamic assays to evaluate the effects of agents at the molecular level. This leads to selection of a biologically effective starting dose and dose escalation schema that can reduce timelines for drug development.66 The 25-mg and 50-mg doses reduced poly(ADP-ribose) (a product of PARP) levels in the tumors and reduced peripheral blood mononuclear cells, with no adverse effects.67

Multiple dosing is necessary for sustained PARP inhibition, because PARP-1 expression has been shown to increase 3 to 6 hours after a single oral dose of veliparib, which coincides with a half-life of 3.64 hours.68,69

Veliparib has also been combined with topotecan, temozolomide, and cyclophosphamide in the treatment of a variety of solid tumors and lymphomas.49-52 In in vivo studies, veliparib enhanced temozolomide tumor growth inhibition and increased the efficacy of temozolomide in cells with high levels of mismatch repair genes.70, 71

In a single-arm phase 2 study of veliparib and temozolomide in 41 patients with metastatic triple-negative breast cancer, the initial dosing of veliparib had to be reduced from 40 mg twice daily on days 1 through 7 to 30 mg twice daily in response to a higher-than-expected incidence of thrombocytopenia.49 Limited activity was seen with the combination, leading to a complete response in 1 patient, a partial response in 2 patients, stable disease in 7, and progressive in 14.49

Topoisomerase I inhibitors bind to the topoisomerase I–DNA complex, which results in accumulation of single- and double-strand DNA breaks. Veliparib has the potential to inflict further damage on the tumor cell by blocking repair of these DNA breaks.52 Veliparib was combined with topotecan in a phase 1 study in patients with solid tumors and lymphomas. The administration schedule had to be adjusted and the topotecan dose reduced in response to myelosuppression.52

Veliparib potentiated DNA damage caused by topotecan, as seen through quantitative detection of the phosphorylation of histone gamma-H2AX, which is a DNA-damage signaling pathway induced by topoisomerase I inhibitors.52

When combined with cyclophosphamide 750 mg/m2 in a study of patients with advanced cancer, veliparib 50 mg twice daily was safe and effective, with only 1 patient experiencing dose-limiting toxicity (ie, thrombocytopenia).51 As a result of the synergistic interaction between veliparib and alkylating agents, veliparib was also studied in combination with doxorubicin and cyclophosphamide.51,53

In this phase 1 trial, veliparib was given in doses ranging from 50 to 150 mg every 12 hours on days 1 through 4, with doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 on day 3 every 21 days; grade 3 febrile neutropenia was the dose-limiting toxicity. The maximum tolerated dose of veliparib was 100 mg twice daily, and the most frequent drug-related toxicities were myelosuppression and fatigue.53

As a single agent or in combination, veliparib has the potential to be useful in several malignancies. As with other PARP inhibitors, myelosuppression is the biggest concern when veliparib is combined with chemotherapy. Phase 2 trials of veliparib as a single agent or in combination with chemotherapy are currently under way in patients with advanced colorectal cancer, melanoma, and ovarian cancer (including BRCA mutation ovarian cancer).

Table 4
POngoing Clinical Trials with PARP Inhibitors
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PARP Inhibitors in Early Development

Table 4
Ongoing Clinical Trials with PARP Inhibitors (Continued)
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Table 4 presents ongoing clinical trials with PARP inhibitors. MK-4827, an inhibitor of PARP-1 and PARP-2, is in phase 1 clinical trials. MK-4827 has shown activity in BRCA mutation cell lines.72 The trials include patients with advanced ovarian cancer, melanoma, glioblastoma multiforme, and other solid tumors. In a recent study, single-agent therapy with MK-4827 showed activity in patients with BRCA mutation tumors and sporadic ovarian cancers.43

The PARP-1 inhibitor AG014699 was first studied in combination with temozolomide in phase 1 and phase 2 trials for metastatic melanoma; however, grade 4 thrombocytopenia occurred in 12% of patients and grade 4 neutropenia occurred in 15%.61 AG014699 is still being investigated in phase 1 trials for advanced solid tumors and in phase 2 trials for advanced BRCA mutation breast and ovarian cancer and as a neoadjuvant treatment in BRCA1 or BRCA2 mutation breast cancer.

In another study presented at ASCO 2011, among patients who received single-agent therapy with AG014699 for BRCA mutation ovarian or metastatic breast cancer, the ORR was 5%; however, 26% of patients had stable disease for ≥4 months.42

The IV PARP-1 and PARP-2 inhibitor INO-1001 was studied in combination with temozolomide in a phase 1b trial that enrolled 12 patients with unresectable stage III or IV melanoma.62 INO-1001 was administered in doses of 100, 200, and 400 mg IV for 1 hour every 12 hours, for a total of 10 doses.62

Myelosuppression and increased liver transaminase levels were the dose-limiting toxicities at the 400-mg dose. One patient had a partial response and 4 had stable disease. The median time to progression was 2.2 months.62

Trials involving the PARP-1 and PARP-2 inhibitors AZD2461 and CEP-9722 are currently under way. AZD2461 is being studied as a single agent for advanced solid tumors. CEP-9722 is being studied in advanced solid tumors as single-agent therapy, in combination with temozolomide, and in combination with gem­citabine and cisplatin.

Conclusion
The results of recent studies have demonstrated the effectiveness of PARP inhibitors against cancers in patients harboring BRCA mutations. The main mechanism of action of PARP inhibitors is hypothesized to be their inhibition of base excision repair and homologous recombination pathways in tumor cells. Other than treating tumors that harbor BRCA mutations, these agents have been hypothesized to extend their benefits to tumors with dysfunctional homologous repair (the concept of “BRCAness”).

The phenotypic similarities between BRCA1 mutation breast cancer and triple-negative breast cancer led to the testing of PARP inhibitors in patients with these cancers.

The benefits of PARP inhibitors will have to be weighed against their long-term toxicities, especially as adjuvant trials in breast cancer get underway. Follow-up assessments of the risk of secondary neoplasia are important.

PARP inhibitors are novel agents whose strength lies in targeting the weakness of tumors, leading to improved outcomes. The results of ongoing clinical trials will help us determine whether these agents will be effective in a wide range of tumors or only in the subset of BRCA mutation carriers.

Author Disclosure Statement
Dr Hopps, Dr Kurkjian, and Dr Pant reported no conflicts of interest.


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