	PARP inhibitors represent an exciting new class of anticancer agents and are currently being evaluating in phase III for a number of different indications. Clinically, PARP inhibitors demonstrate activity in tumors which lack a functional homologous recombination (HR) system and are being developed primarily for patients with germline BRCA1 or BRCA2 mutations and high-grade serous ovarian cancer. This review will discuss the clinical experience with PARP inhibitors so far and the current registration strategies being undertaken. In addition, the review will discuss the rationale behind the recent work combining PARP inhibitors with other targeted agents.

	The Role of PARP and Rationale for Its Inhibition in BRCA-Deficient Tumors

 Poly (ADP-ribose) polymerase (PARP) inhibitors are pharmacologic agents that inhibit the PARP enzymes within the cell. This class of agents represents an exciting potential therapy in patients with defects in the HR repair pathway. In particular, PARP inhibitors are being developed for patients with germline BRCA1 or BRCA2 mutations, although the spectrum of tumors that may be treated effectively by these agents may be larger than this specific population. This article will review: 1) the role of PARP within the cell and why its inhibition is effective in BRCA-deficient tumors; 2) an overview of key clinical trials which have been completed for PARP inhibitors and how they have guided clinical development of these agents; 3) the clinical potential for PARP inhibitors in combination with other targeted agents.

In all human cells, DNA is subjected to frequent damage secondary to environmental insults, toxic metabolites, and DNA replication errors. Single-stranded breaks (SSBs), defined as a loss on continuity in the deoxyribose sugar backbone in one strand of the DNA double helix with the possible loss of the nucleotide base at the site of the break,

 are one of the most frequent mechanisms of damage.

 Detection of SSBs and repair of SSB is thought to require the activity of PARP enzymes as cells that have lost PARP enzymatic activity accumulate SSBs in their DNA. As a consequence of failing to repair SSBs, double-stranded breaks (DSBs) in DNA occur as replication forks encountering SSBs either stall or collapse.

 Fatal if not repaired, 2 major DSB repair pathways have evolved: 1) HR, a largely error-free mechanism to repair DSBs; and, 2) non-homologous end-joining (NHEJ), which randomly attaches DSB together, leading to potentially significant new insertions, deletions, base-substitutions or translocations to a cell’s genome.

The initiation and completion of HR repair is highly dependent on intact BRCA1 and BRCA2 function; therefore, PARP inhibition can potentially lead to tumor cell death in BRCA1/2-deficient tumors. The exact mechanism by which PARP induces cell death in BRCA1/2-deficient tumors is uncertain with 4 mechanisms proposed. First, by failing to repair the DSB through HR, cellular apoptotic pathways are activated leading to cell death. Second, PARP inhibition increases the activity of the NHEJ repair pathway in HR-deficient cells through phosphorylation of DNA-dependent protein kinase substrates, leading to accumulation of genetic errors in essential cellular genes and eventual cellular death secondary to genomic instability.

 Third, it has been proposed that PARP inhibitors work by preventing the release of PARP/BER complex located at a SSB. This “PARP-trapped” BER-repair complex physically prevents progression of replication forks and is thought to require HR-dependent repair in order to remove from DNA.

 Finally, it has been proposed that stalled replication forks can be repaired by either DSB-repair HR or a PARP-dependent HR-repair mechanism, with PARP inhibitors preventing PARP-dependent HR repair.

 In cells which are HR-deficient, inhibition of the PARP activity prevents PARP-mediated HR repair of stalled replication forks, resulting in replication failure and synthetic lethality.

 Helleday’s review on this topic is recommended for any reader interested in further details regarding the mechanism of PARP inhibitors in cancer cells.

		Figure. Presumed Mechanism for Synthetic Lethality Using PARP Inhibitors in BRCA-Deficient Tumors

		Shapiro GI.  Biologic Principles of Targeted Combination Therapy: PARP-1 and Checkpoint Kinase 1 and augmentation of the DNA damage response.  Educational Session, Tumor Biology, American Society of Clinical Oncology, 2012, Chicago, IL. 

Although the focus of this review will be primarily for BRCA1/2-deficient tumors, one should be aware that PARP inhibition may be a theoretical treatment strategy for any tumor with HR-deficiency. Tumors with defects in RAD51, RAD54, DSS1, RPA1, NBS1, or the Fanconi Anemia Pathway should also demonstrate increased sensitivity to PARP inhibition, as well as those with loss of cell checkpoint control.

Phosphatase and tensin homolog (PTEN) deficiency may also result in increased chromosomal instability due to its role in controlling the expression of RAD51 and the cell cycle checkpoint.

Thus, in the future, PARP inhibitors may play a role in a number of genetic subtypes beyond BRCA1 and BRCA2.

Because of the strong interest in PARP inhibitors as a class, a number of pharmaceutical companies have designed PARP inhibitors and have tested them in a number of clinical scenarios. A summary of the agents and their side-effect profiles is shown in table 1. Currently, olaparib, rucaparib, niraparib and BMN673 have reached phase III. Initially thought to be a PARP inhibitor, there were encouraging early results for iniparib in combination with carboplatin plus gemcitabine for patients with triple-negative breast cancer (TNBC); however, this agent was not successful in phase III. Further work into the mechanism of action of iniparib strongly suggests that the drug is not a functional PARP inhibitor but instead works synergistically with chemotherapy to increase DNA damage.

 For this reason, iniparib will not be considered further in this review. In addition, PARP inhibitors have been evaluated as chemosensitizing and radiosensitizing agents, with veliparib primarily used in evaluation; this is beyond the scope of this review but has been extensively reviewed in the past.

 As olaparib, rucaparib and niraparib have been the most extensively studied, they will be the focus of this review.

Olaparib is a potent, orally administered PARP inhibitor with preclinical evidence of in vitro and in vivo activity in HR-deficient cell lines and in combination with alkylating agents.

 Following determination of the dose in phase I,

 3 separate phase II studies evaluated olaparib. In the first studies, olaparib was tested in patients with advanced ovarian cancer with known or suspected BRCA1 or BRCA2 mutations. Overall, 40% of these participants obtained at least a partial response (PR) and appeared to offer more clinical benefit in patients defined as platinum sensitive compared to those who were platinum resistant or refractory (69% vs 45% vs 23% respectively).

Because of these differences it has been proposed that platinum sensitivity in ovarian cancer may be mechanistically related in some way to loss of HR within the tumor cell and may be predictive for PARP inhibitor benefit. The second and third studies evaluated olaparib in confirmed BRCA1- and BRCA2-deficient breast and ovarian cancer, respectively. Both studies treated patients with either high-dose (400 mg twice a day) or lowdose (100 mg twice a day) olaparib; in both studies, high-dose olaparib resulted in superior clinical outcomes and was tolerable, suggesting that higher doses of PARP inhibitors are more efficacious; however, it should be noted that the studies were not randomized and prognostic factors may not be balanced between cohorts. In terms of clinical benefit, 400 mg twice a day of olaparib resulted in response rates of 41% and 33% in breast and ovarian cancer respectively, supporting the use of olaparib in these populations.

		Table 1. Summary of PARP Inhibitors Currently in Development

		BID indicates twice daily; MTD; maximally tolerated dose; LFT, liver function test

Given that TNBC and high-grade ovarian cancer share a number of pathologic features to breast and ovarian tumors with confirmed germline BRCA1 and BRCA2 mutations, it has been hypothesized that these sporadic cancers may have acquired deficiencies in HR repair and may also be sensitive to single agent PARP inhibitors.

 To evaluate this hypothesis, Gelmon and colleagues enrolled patients with TNBC or high grade serous ovarian cancer to receive olaparib 400 mg twice a day with subsequent stratification based on BRCA1/2 mutation status. This study is notable for obtaining a 24% response rate in patients without germline BRCA1/2 mutations. This finding is the first result in clinical trials demonstrating single- agent PARP activity in non—BRCA mutation carriers and offers the first suggestion that a “BRCAness” phenotype may be relevant clinically, although this has not been confirmed through further tumor analysis work.

Because the observations by Gelmon et al suggest the presence of a “BRCAness” phenotype, olaparib may represent a potential maintenance therapy for patients with platinumsensitive, high-grade ovarian cancer. Ledermann and colleagues randomized 265 patients with high-grade serous ovarian cancer to receive either olaparib 400 mg twice a day or placebo. Initially reported in the 

 the most recent interim analysis was reported in 

 A progression-free survival (PFS) was observed in both patients with or without germline BRCA mutations for olaparib compared to placebo, although the PFS was substantially longer in the BRCA-deficient population (BRCA-deficient: 11.2 vs 4.3 months; HR = 0.18; P <0.001) (BRCA-proficient: 7.4 vs 5.5 months; HR = 0.54; P = .0075).

No overall survival benefit has been observed at this point; however, given the number of treatment options available for patients with advanced ovarian cancer, this is not a surprising finding. Maintenance olaparib in combination with single agent carboplatin has also been tested with the combination offering superior PFS (12.2 months vs 9.6 months; HR = .51; 95% CI: 0.34-0.77; P = .0012).

As normal tissues are spared the toxicity of PARP inhibition due to functional HR activity, PARP inhibitors may represent a better tolerated and more efficacious treatment than standard chemotherapy options in patients with germline BRCA1/2 mutations. To assess this question, 97 patients with ovarian cancer with confirmed BRCA1/2 mutations were randomized in a 1:1:1 fashion to receive olaparib 400 mg twice a day, olaparib 200 mg twice a day, or liposomal doxorubicin at its standard dose. Although well tolerated, olaparib failed to demonstrate a PFS benefit compared to liposomal doxorubicin (HR = .88; 95% CI: 0.51-1.56; P = .66).

 This study illustrates some of the challenges that investigators have faced in designing clinical trials evaluating PARP inhibitors. As a topoisomerase II inhibitor, doxorubicin induces DSBs in DNA; theoretically, these types of agents are potentially more efficacious in the BRCA1/2 population than what might be predicted in a non-selected ovarian cancer population.

Because of the biology and chemotherapy responsiveness of BRCA-deficient tumors in general, this situation may be true with other chemotherapy agents as well.

In ovarian cancer, based on the observations of Ledermann et al, the current registration strategy for olaparib has been in the maintenance setting following platinum chemotherapy in both the first line (NCT01874353) and platinum-sensitive settings (NCT01844986) for patients with BRCA-deficient tumors. Olaparib is also being evaluated in phase III for patients with BRCA-deficient breast cancer and is being compared with a physician’s choice of cytotoxic agents (NCT02000622) as well as in the adjuvant setting (NCT02032923).

Rucaparib (AG-014699) is a potent inhibitor of PARP enzymes and was the first PARP inhibitor to be evaluated in clinical settings. Rucaparib was initially formulated for intravenous use with the goal of using it as a chemosensitization agent. Single-agent testing of the agent occurred only after the combination of it with temozolomide proved too toxic and once the drug was converted to oral formulation in order to permit continuous dosing.

 Rucaparib demonstrated clinical activity in BRCA-deficient tumors in doses above 300 mg daily, with a disease control rate of 70%, 2 complete responses and 7 PRs observed in breast cancer, platinum-sensitive and platinumresistant ovarian cancer.

 Rucaparib is also being evaluated in phase III as maintenance therapy for patients with platinum- sensitive ovarian cancer (ARIEL3; NCT01968213); unlike the phase III studies for olaparib, ARIEL3 is not requiring germline BRCA1/2 mutations for enrollment. At the current time, there is no registration strategy being undertaken for rucaparib in BRCA-deficient breast cancer.

	Novel Approaches to Utilizing PARP Inhibitors

Niraparib is a potent oral inhibitor of PARP-1 and PARP-2 and has been evaluated in phase I for BRCA-deficient as well as BRCA-proficient cancers. Clinical activity was observed at doses greater than 60 mg/day with the maximal tolerated dose determined to be 300 mg/day. A subset analysis of patients with BRCA-deficient tumors demonstrated responses in 8/20 ovarian cancers and 2/4 breast cancers.

 Niraparib is currently being evaluated in 2 phase III studies: 1) maintenance therapy in platinum-sensitive, BRCA-deficient ovarian cancer following at least two lines of platinum therapy (NCT018472774); and 2) single-agent therapy compared to physician’s choice of chemotherapy in BRCA-deficient breast cancer (NCT01905592).

Although PARP inhibitors represent an exciting potential treatment option for HR-deficient tumors, it should be recognized that this only represents a small proportion of all cancer and it is unlikely that PARP inhibitors will represent a broad treatment option as single agents. There have been a number of efforts, however, to functionally inhibit HR in cancer cells to allow PARP inhibitors to be used in tumors where initially no benefit would be predicted. Currently, there are 3 such approaches in clinical development.

First, it has been demonstrated in the preclinical setting that phosphatidylinositol-3-phosphate (PI3K) activity is required to maintain HR function and that the addition of the PI3K inhibitor BKM120 downregulated BRCA1/2 activity, sensitizing HR-proficient cells to olaparib.

 This concept has been developed in the clinical setting with early results presented at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting. Although there are encouraging signs of clinical activity, the study enrolled both BRCA-proficient and deficient tumors; without the pending pharmacodynamic analysis, it is not possible to determine at this time whether the combination is responsible for the observed benefit or whether the benefit is due to single-agent activity alone.

Second, as cyclin-dependent kinase-1 (CDK1) phosphorylates BRCA1 and this action is necessary for BRCA1 to efficiently form repair foci at sites of DNA damage and induce the necessary checkpoint arrest, administration of a pharmacologic CDK1 inhibitor could potentially stop HR in HR-proficient tumors; this hypothesis was confirmed in both in vitro and in vivo models.

 Based on this preclinical data, a phase I clinical trial evaluating the combination of veliparib with the CDK1 inhibitor SCH727965 in patients with advanced solid tumors which are HR-proficient is underway (NCT01434316). This trial is in dose escalation and results are not yet available.

Finally, another strategy has been to combine an antiangiogenic agent with PARP inhibitors. In preclinical models, it has been demonstrated that hypoxia down-regulates BRCA1/2 and RAD51 activity, creating a HR-deficient state within the cell; therefore, the utilization of an antiangiogenic agent could increase the clinical efficacy of a PARP inhibitor.

 At the 2014 ASCO Annual Meeting, Liu and colleagues presented phase II results for the combination of cediranib and olaparib in both BRCA-deficient and BRCA-proficient tumors. In this study, 90 patients were enrolled with 48 having BRCA-deficient tumors. The addition of cediranib to olaparib significantly increased the overall response rate (84% vs 56%; P = .008); in addition, responses were observed in BRCA-proficient tumors.

 This combination will be further developed, with phase III studies planned for the near future.

PARP inhibitors represent an exciting new class of anticancer agents and are currently being evaluating in phase III for a number of different indications. In the future, identification of resistance mechanisms and means of overcoming them will have increasing importance in order to maximize benefit. In addition, current work evaluating the combination of PARP inhibitors with other targeted agents appear very promising and have the potential to expand their use beyond BRCA1/ BRCA2-deficient tumors. It is very likely that within the next year, a PARP inhibitor will be approved for clinical use, something that patients with germline BRCA1/BRCA2 mutations, and their physicians, have eagerly been awaiting for the past several of years. 

 John F. Hilton, MD, medical oncologist, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA.

 John Hilton, MD, 450 Brookline Ave, Boston MA, 02215

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PARP inhibitors represent an exciting new class of anticancer agents and are currently being evaluating in phase III for a number of different indications.

John F. Hilton, MD

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