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PARP inhibitors

Introduction

All cancer cells possess defects in DNA repair mechanisms. Poly(ADP-ribose) polymerase 1 (PARP1) plays an important role in DNA repair, with recruitment of PARP1 one of the earliest events in the DNA damage repair response. Inhibition of PARP1 has considerable therapeutic potential in the treatment of various cancers, including ovarian cancer, breast cancer, prostate cancer and non-small cell lung cancer. The predominant mechanism of action of the PARP inhibitors is synthetic lethality, whereby two pathway defects have limited effect separately, but when both are present in the cell become lethal. This synthetic lethality has rendered the PARP1 inhibitors particularly useful in tumors with BRCA1 or BRCA2 loss-of-function mutations. Identification of other biomarkers that may help select for patients for whom PARP inhibitors are likely to be useful remains a significant challenge. This collection of recent high-quality full-text articles from Springer Nature and other prominent publishers provides an overview of the role of PARP1 in DNA repair and the use (and potential) of PARP inhibitors in cancer treatment.

DNA repair mechanisms and the role of PARP

The multifaceted roles of PARP1 in DNA repair and chromatin remodelling

This review discusses the role of poly(ADP-ribose) polymerase 1 (PARP1) in DNA repair, including single-strand break repair, nucleotide excision repair, double-strand break repair and stabilization of replication forks, as well as its role in the modulation of chromatin structure.

Summary
  • Recruitment of poly(ADP-ribose) polymerase 1 (PARP1) is one of the earliest events in the DNA damage response, with induction of various kinds of DNA damage leading to rapid recruitment of PARP1 to the site of damage.
  • Single-strand breaks are rapidly detected and bound by PARP1, and PARP1 may also be important for the repair of single-stranded DNA nicks. PARP1 also plays a role in base excision repair, but unlike single-strand break repair, PARP1 is not essential for base excision repair.
  • PARP1 has also been found to play a role in recognition of damage in global genome nucleotide excision repair, the dominant subpathway of nucleotide excision repair.
  • PARP1 recognizes DNA breaks and is involved in the early recruitment of factors to facilitate double-strand break repair; however, there may be other redundant pathways for activation of this repair process, as deficiency in PARP1 delays, but does not abolish, recruitment of necessary proteins for this process.
  • The DNA damage sensor meiotic recombination 11 (MRE11) nuclease is recruited by activity of PARP1, potentially contributing to DNA-end processing at double-strand breaks, which may lead to repair of double-strand breaks via homologous recombination.
  • PARP1 may increase efficiency of classical non-homologous end joining (NHEJ) repair – and may aid in the recruitment of the MRE11–RAD50–NBS1 (MRN) complex to sites of double-strand breaks.
  • Evidence suggests that PARP1 may also play a role in the DNA replication process via numerous proteins involved in DNA replication, as well as being involved in the response to replicative stress, including regulation of the DNA replication fork progression and processing in replication stress.
  • PARP1 has also been implicated in the modulation of chromatin structure – facilitating repair in response to various types of DNA damage.

Chaudhuri AR, Nussenzweig A. Nat Rev Mol Cell Biol 2017;18:610–621. doi:10.1038/nrm.2017.53

Synthetic lethality and introduction to PARP inhibitors

Overview of PARP inhibitor design and optimization

This chapter briefly summarizes the rationale and discovery process for the poly(ADP-ribose) polymerase-1 (PARP1) inhibitors in oncology, and reviews the agents currently in clinical development.

Summary
  • Inhibition of poly(ADP-ribose) polymerase (PARP)1/2 combined with DNA damaging chemotherapeutics or radiation, or alone in cells already deficient in certain DNA repair mechanisms, compromises cancer cell DNA repair mechanisms, leading to genomic dysfunction and cell death.
  • The discovery and development of the pharmacophore for PARP inhibitors started with the discovery of the role of substituted benzamides, then of bicyclic aryl amides as sub micromolar inhibitors, and subsequently, benzimidazole caboxamides, which provided a potent, compact, easily derivatizable core scaffold.
  • While there are over 20 drug discovery groups designing PARP inhibitors, the current clinical compounds are remarkably similar. Factors that may distinguish these agents include their PARP trapping ability and their susceptibility to efflux transporters.
  • The PARP inhibitors have yet to demonstrate clear efficacy when used in combination with chemotherapeutics, and may do better as single agent therapy in patients with tumors deficient in certain DNA repair pathways.

Ferraris D. In: PARP inhibitors for cancer therapy. Edited by Curtin N, Sharma R. Humana Press. 2015:183–203. doi:10.1007/978-3-319-14151-0_7

Synthetic lethality and cancer

The review explores the advances made and challenges of exploiting the genetic phenomenon of synthetic lethality to indentify new anticancer therapeutic targets.

Summary
  • A synthetic lethal interaction is one in which a mutant tumor cell requires activity of a synthetic lethal partner gene for viability.
  • Screening for synthetic lethal interactions poses three main challenges:
    • These interactions result in lethality
    • Many are condition dependent (the interaction is dependent upon intrinsic conditions [genetic background, metabolic state of the cell] or extrinsic conditions [cellular microenvironment, exposure to therapeutic agents])
    • They are rare and many combinations need to be queried to identify such interactions.
  • In addition to loss-of-function and reduction-of-function, synthetic lethality approaches may also be able to target synthetic dosage lethality – which is a genetic interaction where overexpression of one gene combined with reduction in function of another gene results in lethality, as well as conditional synthetic lethality – targeting condition-dependent genetic interactions.
  • High-throughput screening approaches are necessary to identify synthetic lethal interactions. The use of model organisms such as yeast is one approach.
  • Another approach to screening for synthetic lethality is using human cells – an approach that has been transformed by the discovery of CRISPR.
  • Both RNA interference and CRISPR play important roles for human genome-wide screening.
  • Translation of synthetic lethality into clinical therapeutics has only been successful so far for the interaction between poly(ADP-ribose) polymerase-1 (PARP1) and the breast cancer susceptibility genes BRCA1 and/or BRCA2.
  • Integration of data from the following three platforms that provide information on synthetic lethal candidates may help increase the probability of finding true interactions for therapeutic targeting:
    • conservation from model organism genetic networks
    • human synthetic lethality screening
    • in silico predictions.

O'Neill NJ, Bailey ML, Hieter P. Nat Rev Gen 2017;18:613–623. doi:10.1038/nrg.2017.47

PARP inhibitors in ovarian cancer

Delivering widespread BRCA testing and PARP inhibition to patients with ovarian cancer

In this paper, key clinical trials of poly(ADP-ribose) polymerase (PARP) inhibitors are summarized, and the place of the PARP inhibitors in the treatment of ovarian cancer is explored, with a focus on the importance of testing for BRCA and other biomarkers.

​​​​​​​Summary
  • Currently in ovarian cancer, poly(ADP-ribose) polymerase (PARP) inhibitors act via synthetic lethality – whereby two pathway defects have limited effect separately, but when both are present in the cell, become lethal – combining PARP inhibition with BRCA1 or BRCA2 loss-of-function mutations.
  • The first PARP inhibitor, olaparib, has been licensed for the treatment of patients with BRCA-mutation-positive ovarian cancer. Several other agents are also in late-phase clinical development.
  • Knowledge of a patient’s BRCA-mutation status provides important prognostic information and can be used to guide treatment decisions. Patients now have the opportunity to receive a PARP inhibitor as part of their routine care, therefore it is important that the BRCA mutation status of each patient is known prior to treatment.
  • Selective use of BRCA-mutation testing based on family history fails to identify a significant proportion of patients with ovarian cancer harboring BRCA mutations – testing must be considered an important and routine part of the diagnostic process.
  • To address increasing demand, and to enable rapid access to BRCA mutation testing, several new models of genetic testing have been developed that integrate oncology and genetics.
  • Implementation of widespread BRCA testing is crucial to the success of PARP inhibitor therapy in ovarian cancer. An important barrier to such testing is access to funding.
  • Identification of the optimal time for PARP inhibitor therapy in ovarian cancer is an important issue that remains to be fully addressed. Questions include whether these agents should be used as a treatment for relapsed ovarian cancer, or as a maintenance strategy following response to platinum-containing agents, and what is the most appropriate line of therapy, and if treatment should be dependent on platinum-sensitivity.
  • The presence of a pathogenic BRCA1 or BRCA2 mutation is currently the best predictive biomarker for successful PARP inhibitor therapy. Challenges associated with these agents include identification of additional patients likely to benefit from such treatment, enhancement of PARP inhibitor activity and overcoming resistance.

George A, Kaye S, Banerjee S. Nat Rev Clin Oncol 2017;14:284–296. doi:10.1038/nrclinonc.2016.191

What is the place of PARP inhibitors in ovarian cancer treatment?

This review summarizes clinical experience and ongoing clinical trials with the poly(ADP-ribose) polymerase-1 (PARP1) inhibitors in ovarian cancer.

Summary
  • Activity of a poly(ADP-ribose) polymerase (PARP) inhibitor as monotherapy was first demonstrated in a phase I trial of olaparib, with a phase II trial confirming activity in ovarian cancer patients with a germline BRCA mutation. These patients had received a median of three prior lines of therapy and response rates were higher for platinum-sensitive than for platinum-resistant cancers.
  • A phase II trial of veliparib as monotherapy also showed some activity, with higher response rates again seen in platinum-sensitive patients. Phase I studies for the PARP inhibitors niraparib and rucaparib also demonstrated activity as monotherapy in germline BCRA-mutated ovarian cancers. Talazoparib is currently being studied as monotherapy in BRCA-mutated advanced solid tumors and in germline BRCA-mutated ovarian cancer that has progressed through treatment with any other PARP inhibitor.
  • A growing body of evidence suggests that patients who have BRCA-non-mutated tumors may also respond to PARP inhibition. A challenge in the development of these agents for such patients is the identification of a biomarker suggesting the presence of homologous recombination deficiency.
  • Clinical trials have demonstrated improvements in progression-free survival with use of a PARP inhibitor following a response to chemotherapy, compared with placebo; an important reason why the PARP inhibitors are an attractive option for maintenance therapy following a response to standard chemotherapy is their relatively low toxicity.
  • The effects of the PARP inhibitors may be able to be enhanced by use in combination with certain chemotherapeutics that act to potentiate DNA damage, although one challenge to overcome in this approach is an increase in hematological toxicities.
  • Several studies have investigated the use of PARP inhibitors in combination with other therapies, to either expand the population in which PARP inhibitors may exhibit clinically relevant activity or to prevent the development of resistance. An example of such a combination is that of olaparib and the anti-angiogenic agent cediranib – a combination shown to have most benefit in wild-type or unknown BRCA-mutation status patients.

Liu JF, Matulonis UA. Curr Oncol Rep 2016;18:29. doi:10.1007/s11912-016-0515-z

Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: An updated analysis from a randomized, placebo-controlled, double-blind, phase 2 trial

This paper presents an updated overall survival analysis of Study 19, a randomized, double-blind, placebo-controlled, multicenter phase II trial of olaparib maintenance monotherapy in platinum-sensitive recurrent serous ovarian cancer.

Summary
  • Study 19 demonstrated that olaparib maintenance monotherapy significantly improves progression-free survival versus placebo in patients with platinum-sensitive recurrent serous ovarian cancer. The analysis described here was conducted to assess the effect of maintenance olaparib on overall survival.
  • Study 19 included 265 patients (136 with deleterious BRCA mutations) with recurrent ovarian, fallopian tube or primary peritoneal platinum-sensitive serous cancer; patients were required to have received at least two previous courses of platinum-based chemotherapy with a partial or complete response to their most recent regimen.
  • Patients were randomized to receive oral olaparib 400 mg twice daily as maintenance monotherapy or matching placebo until disease progression.
  • At the time of this analysis, at which time the median follow-up for survival for olaparib and placebo recipients was 71.0 and 70.8 months, respectively, the Cox proportional hazards analysis suggested an overall survival advantage, although not meeting the required threshold for statistical significance, for olaparib monotherapy over placebo, with a hazard ratio (HR) 0.73 (95% confidence interval [CI] 0.55–0.96; nominal p=0.025).
  • Olaparib monotherapy was also associated with an overall survival advantage, although again not reaching statistical significance, among the subgroup of patients with BRCA-mutated cancer, with a HR of 0.62 (95% CI 0.41–0.94; nominal p=0.025).
  • This updated survival analysis suggests a survival advantage with olaparib monotherapy compared with placebo in patients with platinum-sensitive recurrent serous ovarian cancer.

Ledermann JA, Harter P, Gourley C et al. Lancet Oncol 2016;17:1579–1589. doi:10.1016/S1470-2045(16)30376-X

PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: Current practice and future directions

This paper reviews the role of BRCA proteins and poly(ADP-ribose) polymerase-1 (PARP1) inhibitors in ovarian cancer, with a summary of ongoing clinical studies with PARP inhibitors.

Summary
  • Patients with a deleterious germline BRCA1/2 mutation have an estimated lifetime risk by age 70 for developing ovarian cancer of 40% for BRCA1 and 11–18% for BRCA2, with corresponding risks for breast cancer of 57–65% and 45–49%, respectively.
  • There are currently six primary pathways that have been identified for DNA repair. In response to DNA damage, proteins comprising repair complexes are recruited to the site of damage; loss or reduction in function in such proteins can result in impaired DNA repair. The BRCA1/2 proteins mediate what may be the rate-limiting step in homologous recombination, one of the six identified DNA repair pathways.
  • PARP1, PARP2, and PARP3 have been implicated in DNA repair. Certain types of DNA damage result in an about a 500-fold increase in PARP1 catalytic activity; PARP1 functions in a number of DNA repair pathways.
  • There are four proposed models for how PARP inhibitors may instigate synthetic lethality (when two genetic lesions that individually are not lethal, become lethal when combined in a cell):
    • inhibition of base excision repair,
    • trapping PARP1 on damaged DNA,
    • defective recruitment of BRCA1 to damaged DNA,
    • activation of non-homologous end joining.
  • There are several PARP inhibitors currently approved or in late-stage clinical development. These agents demonstrate differences in bioavailability, molar equivalence of PARP enzyme inhibition, and PARP trapping capability.
  • Clinical challenges for the PARP inhibitors include:
    • a lack of validated biomarkers to predict patients with sporadic ovarian cancer who may respond to PARP inhibitors,
    • inherent or acquired resistance to PARP inhibitor therapy,
    • long-term safety,
    • need for more widespread genetic testing,
    • cost is an important challenge.
  • Further clinical studies are necessary to better understand when and how to sequence therapy, which combination strategies potentiate PARP inhibitor antitumor activity, and the long-term toxicities of these agents.

Konecny GE, Kristeleit RS. Brit J Cancer 2016;115:1157–1173. doi:10.1038/bjc.2016.311

Quality of life during olaparib maintenance therapy in platinum-sensitive relapsed serous ovarian cancer

This paper reports on the impact of olaparib on health-related quality of life (HRQoL) and disease-related symptoms in a phase II study in patients with platinum-sensitive relapsed serous ovarian cancer.

Summary
  • Study 19 was a phase II placebo-controlled study of maintenance olaparib 400 mg twice daily in adults with platinum-sensitive, relapsed, high-grade serous ovarian cancer who had received at least two platinum-based regimens and had a partial or complete response to their most recent platinum-based regimen. Of the 265 patients enrolled, BRCA1/2 mutation status was available for 254 patients, of whom 136 had a known/suspected deleterious germline BRCA1/2 mutation and/or somatic BRCA1/2 mutation.
  • HRQoL was assessed using the Functional Assessment of Cancer Therapy Ovarian (FACT-O) questionnaire, with the Trial Outcome Index (a subset analysis of the FACT-O) the primary HRQoL measure. The Functional Assessment of Cancer Therapy/National Comprehensive Cancer Network Ovarian Symptom Index (FOSI) – an assessment derived from eight symptom-related FACT-O items – was also used.
  • Compliance rates for TOI, FOSI and FACT-O assessments were high at baseline, and similar in each arm (all over 80%), and overall compliance rates remained high over the 16 months for the study at 69% or 70% for all three assessments in both patient groups.
  • Median progression-free survival was 4.8 months in the placebo arm, hence most placebo patients did not contribute HRQoL data beyond 6 months, so no data are presented beyond 6 months.
  • Overall, and for the BRCA mutated and germline BRCA mutated groups, most patients achieved best HRQoL responses of no change. There were no statistically significant differences in rates of improvement as measured by TOI, FOSI and FACT-O.
  • Patients experience of important symptoms on FOSI, and both TOI and FACT-O total scores, were consistent with baseline and comparable between treatment groups over time; there were minimal changes over time in nausea, vomiting and fatigue.
  • The authors conclude that maintenance treatment with olaparib does not appear to adversely affect HRQoL compared with placebo, a finding supported by high compliance with treatment and very low discontinuation rates because of adverse events.

Ledermann JA, Harter P, Gourley C, et al. Brit J Cancer 2016;115:1313–1320. doi:10.1038/bjc.2016.348

Targeting DNA repair and replication stress in the treatment of ovarian cancer

This review examines the rationale behind and strategies for DNA repair inhibitors and cell cycle checkpoint inhibitors, as single agent therapy and in combination with DNA damaging agents in ovarian cancer.

Summary
  • Pathways for DNA repair include base excision repair, nucleotide excision repair, mismatch repair, homologous recombination, nonhomologous end joining, alternative end joining and translesion DNA synthesis. Removal of DNA adducts should also be considered as a category of DNA repair.The concept behind inhibitors of DNA repair is that inhibition of DNA repair leads to accumulation of DNA damage and ultimately to cell death.
  • One challenge in ovarian cancer research is that of overcoming resistance to DNA damaging agents.  To prioritize the genes that should be targeted, and identify dominant genes for drug sensitivity, screening methods including shRNA and siRNA screening, CRISPR/Cas9 screening, and genetic screening with DNA repair gene-mutant cell library are used.
  • Identifying druggable proteins among the target genes is the next challenge. Ideally, DNA repair inhibitors should induce synthetic lethality under specific conditions, and should have relatively low toxicity.
  • Poly(ADP-ribose) polymerase-1 (PARP1) inhibitors act as DNA repair inhibitors by first accumulating unrepaired single-strand breaks via catalytic inhibition of PARylation, then progressing replication forks collide with these breaks, converting them into double-strand breaks. Homologous recombination is then needed for repair, and cells with a deficiency in this pathway subsequently die from accumulation of double-strand breaks.
  • The five clinical PARP inhibitors vary markedly in cytotoxicity, with much of this variation explained by an additional mechanism of action, damaging DNA via PARP trapping, which results in highly cytotoxic PARP-DNA complexes; for the five clinical PARP inhibitors, their ranking for cytotoxicity is talazoparib ≫ niraparib ≅ olaparib ≅ rucaparib > veliparib, which corresponds to their PARP trapping potencies.
  • The cell cycle is rapidly halted in response to replication stress, to allow repair and avoid further damage. Inhibitors of cell cycle checkpoints as single agents, can kill cancer cells with intrinsic high replicative stress. Inhibitors of several checkpoint protein kinases ATR, CHK1 and WEE1 are promising drugs currently undergoing assessment in ovarian cancer.

Murai J. Int J Clin Oncol 2017;22:619–628. doi:10.1007/s10147-017-1145-7

Patient counseling and management of symptoms during olaparib therapy for recurrent ovarian cancer

This paper reviews the safety and tolerability of olaparib in patients with ovarian cancer, and summarizes a practical approach to supportive care in such patients.

Summary
  • To characterize the safety and tolerability of olaparib, the researchers searched PubMed for prospective studies of olaparib in recurrent ovarian cancer.
  • In the safety database for the FDA-approved indication, the most frequent adverse events (AEs; ≥20%) across six studies were fatigue (including asthenia), nausea, abdominal pain/discomfort, vomiting, anemia, diarrhea, nasopharyngitis/upper respiratory infection, dyspepsia, decreased appetite, myalgia, and arthralgia/musculoskeletal pain; the most frequent laboratory abnormalities (≥25%) of all grades were increase in creatinine and mean corpuscular volume elevation and decreases in hemoglobin, lymphocytes, absolute neutrophil count, and platelets.
  • Differences in the toxicity of olaparib in patients with ovarian cancer compared with other solid tumors have been reported, hence special attention and early intervention to maintain dose intensity and prevent unnecessary drug discontinuation is recommended in this patient population.
  • An analysis of maintenance study data showed that nausea, vomiting, fatigue and anemia occurred early during treatment, but were generally transient, resolving with supportive care.
  • Fatigue and gastrointestinal (GI) toxicities can be problematic in ovarian cancer as patients may have baseline disease-related fatigue and GI symptoms. Prophylactic measures should thus be discussed and enacted to minimize GI toxicities from the time of treatment initiation.
    • All patients taking olaparib should be screened for fatigue, with its management part of routine care.
    • Addressing nausea and vomiting proactively and aggressively is important for maintaining adherence without significant deterioration in quality of life.
    • Dose interruption followed by dose modification of olaparib is acceptable for managing significant treatment-related diarrhea.
    • Discussing the possibility of dyspepsia and dysgeusia with patients, along with early initiation of proton pump inhibitors, can help minimize dyspepsia-related discomfort.
  • It is important that patients and caregivers be counseled on potential AEs and made aware that many of these can be effectively managed so that therapy can continue.

Moore KN, Monk BJ. Oncologist 2016;21:954–963. doi:10.1634/theoncologist.2015-0268

PARP inhibitors in other cancers

PARP inhibitors in breast cancer: Latest evidence

This paper reviews the results of clinical trials of the poly(ADP-ribose) polymerase-1 (PARP1) inhibitors in breast cancer, as well as other important ongoing trials.

Summary
  • As monotherapy, the poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated excellent efficacy and are generally well tolerated. However, results for these agents when used in combination with cytotoxic chemotherapy are more variable, with benefit often hampered by amplification of hematological toxicities.
  • Olaparib:
    • Phase III results (OlympiAD trial) for monotherapy indicate potential for olaparib in germline BRCA mutation-positive metastatic breast cancer after progression on standard chemotherapy.
    • Testing is underway as adjuvant monotherapy in early-stage germline BRCA mutation-positive breast cancer.
    • Unacceptable toxicity when combined with platinum chemotherapy.
  • Talazoparib:
    • Ongoing phase III trial (EMBRAC) assessing single-agent therapy in germline BRCA mutation-positive metastatic breast cancer patients who progress on standard chemotherapy regimens versus physician’s choice of chemotherapy.
    • Ongoing trial as neoadjuvant monotherapy in early-stage germline BRCA mutation-positive breast cancer.
    • Unacceptable toxicity when combined with platinum chemotherapy.
  • Rucaparib:
    • Not yet reached phase III in breast cancer.
    • Appears to be tolerable when combined with platinum chemotherapy but efficacy remain to be seen for metastatic disease.
  • Veliparib:
    • Not yet reached phase III in breast cancer.
    • In combination with platinum chemotherapy did not show additional benefit over carboplatin plus standard neoadjuvant therapy.
    • Ongoing phase III trial (BROCASE3) assessing impact of adding veliparib to carboplatin + paclitaxel in germline BRCA mutation-positive metastatic disease.
  • Other agents:
    • Niraparib: phase III trial of monotherapy stopped due to patient dropout.
    • CEP-9722: currently in early phases of development.
  • The question of whether the PARP inhibitors will be of use in breast cancer patients without germline BRCA mutations remains. Investigations to better identify patients likely to benefit from PARP inhibitors are ongoing.

Ponec RM, Peddi R, Callahan RD. Curr Breast Cancer Rep 2017;9:188–194. doi:10.1007/s12609-017-0251-x

Olaparib for metastatic breast cancer in patients with a germline BRCA mutation

This paper reports the findings of the OlympiAD trial, a randomized, open-label, phase III study of olaparib monotherapy versus standard therapy in metastatic breast cancer patients with a germline BRCA mutation.

Summary
  • The OlympiAD trial was a randomized, controlled, open-label, multicenter, international, phase III study designed to compare efficacy and safety of olaparib with that of standard single-agent chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer and a germline BRCA mutation.
  • A total of 302 patients were randomized, in a 2:1 ratio, to olaparib (300 mg twice daily) or standard therapy (capecitabine, eribulin mesylate or vinorelbine); the primary endpoint was progression-free survival (PFS).
  • Median PFS was significantly longer for olaparib than standard therapy (7.0 months vs 4.2 months; hazard ratio 0.58; 95% confidence interval [CI], 0.43–0.80; p<0.001).
  • The response rate was 59.9% in the olaparib group and 28.8% in the standard therapy group, with complete response in 9.0% in the olaparib group and 1.5% in the standard-therapy group.
  • The rate of grade 3 or higher adverse events was lower in the olaparib group than in the standard therapy group, at 36.6% and 50.5%, respectively.
  • Treatment discontinuation due to adverse events occurred in 4.9% of patients in the olaparib group compared with 7.7% of those receiving standard therapy.
  • These results show that, among patients with HER2-negative metastatic breast cancer and a germline BRCA mutation, median PFS was significantly longer for oral olaparib monotherapy than standard chemotherapy.

Robson M, Im S-A, Senkus E, et al. N Engl J Med 2017;377:523–533. doi:10.1056/NEJMoa1706450

PARP Inhibitors in prostate cancer

This review examines the molecular rationale behind the poly(ADP-ribose) polymerase-1 (PARP1) inhibitors, reviews clinical experience to date, and explores the future of such therapy in prostate cancer.

Summary
  • There are two main roles for poly(ADP-ribose) polymerase-1 (PARP-1) on chromatin: DNA damage repair and transcriptional regulation. There has been a substantial body of research into the role of PARP-1 in prostate cancer, leading to important discoveries, including its role regulating the function of the ETS family of transcription factors, which play an important role in prostate cancer.
  • Evidence for clinical benefit of PARP inhibitors in cancer came initially from the pivotal phase I trial of olaparib in solid tumors. Important studies in patients with prostate cancer include the TOPARP-A study – a phase II study of olaparib in 50 heavily treated patients with metastatic castration-resistant prostate cancer (mCRPC) that showed promising results. These results led to the FDA designating olaparib as breakthrough therapy in this subset of mCRPC patients.
  • To date, the safety profile of the PARP inhibitors has been manageable, with the most commonly reported side effects being hematological and gastrointestinal toxicities and fatigue.
  • The therapeutic rationale for PARP inhibitors in combination therapy involves the following:
    • Increasing DNA damage thus enhancing dependence on PARP-mediated DNA repair,
    • Increasing trapped PARP-DNA complex formation,
    • Induction and maintenance of BRCAness phenotype for synthetic lethality.
  • The PARP inhibitors have been evaluated in combination with chemotherapeutics, androgen-deprivation therapy, ionizing radiation, targeting agents and immunotherapy.
  • Newer drug delivery strategies have been evaluated in preclinical studies, demonstrating that nanoparticle formulations of olaparib and talazoparib are a safe platform for intravenous and intraperitoneal delivery.
  • Comprehensive profiling of the genomic, epigenomic, transcriptomic, and proteomic changes in prostate cancer is a reality and this information is guiding patient selection in PARP inhibitor trials. Biomarkers for PARP inhibitors are classified broadly into markers of DNA repair deficiency, transcription regulation, and cell cycle control. Although multiple genes and pathways hold promise, the search for an ideal biomarker continues.
  • Challenges associated with the use of the PARP inhibitors include the development of resistance, for which at least four mechanisms have been proposed. Patient selection and timing of PARP inhibitor therapy in prostate cancer also remain to be determined.

Geethakumari PR, Schiewer MJ, Knudsen KE, Kelly WK. Curr Treat Options in Oncol 2017;18:37. doi10.1007/s11864-017-0480-2

Smoking history predicts sensitivity to PARP inhibitor veliparib in patients with advanced non–small cell lung cancer

This paper reports the findings of an exploratory analysis evaluating the impact of smoking status on clinical outcomes using data from the M10-898 study of veliparib in previously untreated non-small cell lung cancer added to carboplatin and paclitaxel.

Summary
  • The M10-898 study was a multicenter, randomized, double-blind, placebo-controlled phase II trial of previously untreated advanced non-small cell lung cancer, in which patients were randomized to veliparib or placebo in combination with carboplatin/paclitaxel, stratified by histologic subtype and patient-reported smoking history (recent smoker, former smoker, or never-smoker).
  • In the overall population, median progression-free survival (PFS) was 5.8 months in the veliparib group versus 4.2 months in the placebo group.
  • In the recent smoker group, median PFS was 5.6 months for veliparib versus 3.3 months for placebo (hazard ratio [HR] = 0.38, 95% confidence interval [CI]: 0.21–0.67, p<0.01). Median overall survival (OS) was 12.5 months and 5.4 months in the veliparib and placebo groups, respectively (HR = 0.43, 95% CI: 0.26–0.70, p<0.01). Statistically significant improvement was not observed in former smokers and never-smokers for PFS.
  • Smoking history was the only factor with a significant interaction with study treatment. On multivariate analysis, self-reported smoking within 12 months of study entry was the single factor most predictive of benefit with veliparib.
  • The rate of grade 3 or 4 adverse events was higher in both the overall population and in the recent smokers subgroup with veliparib treatment than with carboplatin/paclitaxel.
  • The efficacy of veliparib in recent smokers may be a reflection of the effect of veliparib on DNA repair pathways and in reducing genomic instability.

Reck M, Blais N, Juhasz E, et al. J Thorac Oncol 2017;12:1098–1108. doi:10.1016/j.jtho.2017.04.010

Combination strategies

Combination of PARP inhibitors with clinical radiotherapy

This chapter reviews the rationale for the poly(ADP-ribose) polymerase-1 (PARP1) inhibitors as radiosensitizers and discusses challenges associated with their use in clinical practice. Current clinical development is also reviewed.

Summary
  • While all cancer cells possess defects in DNA repair mechanisms, the identification of specific defects leads to the possibility of targeted manipulation of this response to radiosensitize tumors to a greater degree than normal tissue.
  • Potential mechanisms by which the PARP inhibitors may achieve radiosensitization include:
    • conversion of radiation-induced single strand DNA breaks to double-strand breaks during DNA replication,
    • accumulation in tumor cells,
    • via a vasodilatory effect (may reduce hypoxia - an important cause of radioresistance),
    • antiangiogenic effects on tumor cell vasculature,
    • radiosensitizing both acutely hypoxic and oxygenated cancer cells,
    • potentially increasing killing of undifferentiated cancer stem cells, thus reducing the probability of local recurrence after radical radiotherapy.
  • While there is little systemic toxicity when used as monotherapy, combining PARP inhibitors with concomitant chemoradiotherapy may be associated with significant toxicity. It may be possible to overcome this barrier to combination therapy, for example by using lower concentrations of PARP inhibitor, and by careful scheduling of chemotherapy and PARP inhibitor during radiotherapy.
  • Challenges in terms of clinical trial design for use of radiotherapy and the PARP inhibitors include finding the maximum tolerated dose, assessing toxicities and appropriate radiotherapy planning.
  • Several early-phase clinical studies combine PARP inhibitors with radiotherapy:
    • olaparib for esophageal carcinoma,
    • veliparib (ABT-888) and capecitabine-based chemoradiotherapy for rectal carcinoma,
    • veliparib for brain metastases,
    • veliparib in recurrent or inflammatory breast cancer,
    • olaparib for locally advanced non-small cell lung cancer.
  • The prospect of using pharmacological inhibition of DNA repair to overcome tumor radioresistance is an exciting one, that may signal “the dawning of a new treatment frontier in radiation oncology”.

Carruthers R, Chalmers AJ. In: PARP inhibitors for cancer therapy. Edited by Curtin N, Sharma R. Humana Press. 2015:533–551. doi:10.1007/978-3-319-14151-0_23

Clinical trials of PARP inhibitors with chemotherapy

This chapter reviews clinical trials of poly(ADP-ribose) polymerase-1 (PARP1) inhibitors in combination with methylating agents, cyclophosphamide, platinum agents, paclitaxel, topoisomerase poisons, combination chemotherapy or vascular endothelial growth factor inhibiting agents. 

Summary
  • The PARP inhibitors were first investigated as add-on to chemotherapeutics, to overcome tumor resistance. With the discovery of synthetic lethality, the opportunities for combination therapy widened.
  • It was thought that combination therapy with methylating agents such as temozolomide and dacarbazine might suppress base excision repair via PARP inhibition to accentuate the cytotoxicity of strand breaks induced by methylating agents and thus increase the tumor cell kill. This combination therapy is limited by hematological toxicity, requiring reduction in methylating agent dosage, but results of phase II trials demonstrated some promising signs of efficacy.
  • In trials investigating combining PARP Inhibitors with cyclophosphamide, results indicated that while this combination is well tolerated and phase I trial results were promising, phase II trial results indicated little or no improvement in response rates with the addition of the PARP inhibitor.
  • Combining PARP inhibition with platinum agents may potentiate the tumoricidal effects of these drugs by suppressing lesion repair and may help reduce resistance. Trials conducted to date have demonstrated promising antitumor activity with this combination.
  • A phase II trial investigating combining olaparib and paclitaxel in recurrent or metastatic gastric cancer demonstrated a significant increase in overall survival compared with paclitaxel plus placebo. This treatment combination is being investigated in a phase I/II trial in metastatic triple-negative breast cancer.
  • PARP inhibitors may potentiate the toxicity of topoisomerase poisons by suppression of single-strand break repair. However, early clinical trials found a high incidence of hematological malignancies, leading to difficulties in identifying optimal dosing strategies to enable the full potential of this combination to be evaluated. Results to date indicate this combination therapy is potentially useful, particularly in BRCA-mutant breast cancers.
  • When combined with combination chemotherapy, dose-limiting hematological toxicity is an important issue, although promising efficacy has been demonstrated.
  • A direct relationship between PARP inhibition and angiogenesis has been suggested, although published evidence combining PARP inhibitors and vascular endothelial growth factor (VEGF) inhibitors is limited to two small phase I trials – notably, hematological toxicity with this combination was minimal.

Clift A, Coupe N. In: PARP inhibitors for cancer therapy. Edited by Curtin N, Sharma R. Humana Press. 2015:511–531. doi:10.1007/978-3-319-14151-0_22

Resistance to PARP inhibitors

Resistance to PARP inhibitors mediated by secondary BRCA1/2 mutations

This chapter reviews the mechanisms behind the development of resistance to poly(ADP-ribose) polymerase-1 (PARP1) inhibitors, with a focus on BRCA1/2 restoration.

Summary
  • While the PARP inhibitors have shown great promise, there is evidence that resistance to this therapy can develop. An important mechanism for this resistance is that of restoration of functional homologous recombination repair (HRR) via secondary BRCA1/2 mutation in BRCA1/2-mutated tumors.
  • An important mechanism of action of the PARP inhibitors is synthetic lethality – inhibition of PARP activity and loss of double strand break repair by HRR are lethal to cells when both defects are present. This synthetic lethality makes the PARP inhibitors particularly useful in the treatment of tumors with defects in double strand break repair by HRR; the BRCA1 and BRCA2 proteins are key players in HRR.
  • Synthetic lethality can also occur from non-BRCA-associated loss of HRR function, in many different cancer types – with changes in expression of a number of genes involved in HRR shown to correlate with PARP inhibitor response.
  • There are several purported mechanisms for the development of PARP inhibitor resistance. The main mechanism is thought to be restoration of HRR function by secondary BRCA1/2 mutation. The researchers propose a model of acquired resistance to PARP inhibitors and platinum compounds by restoration of HRR due to secondary BRCA1/2 mutations in BRCA1/2-mutated cancer.
  • Another possible mechanism for PARP inhibitor resistance is upregulation of genes that lead to efflux of the drug out of neoplastic cells.
  • It has also been reported that loss of or reduced 53BP1 expression renders cells less sensitive to PARP inhibition, hence this may be another mechanism by which cells become resistant to these inhibitors.
  • Two further possible mechanisms are: BRCA1 stabilization coupled with 53BP1 deficiency, and loss of PARP1 expression.
  • To determine the prevalence of the mechanisms described, as well as identify other mechanisms of PARP inhibitor resistance, there needs to be considerable effort made to collect and analyze clinical samples of PARP inhibitor-resistant cancers.

Dhillon KK, Taniguchi T. In: PARP inhibitors for cancer therapy. Edited by Curtin N, Sharma R. Humana Press. 2015:431–452. doi:10.1007/978-3-319-14151-0_18