PARP Inhibitors in Prostate Cancer—The Preclinical
Rationale and Current Clinical Development

Prostate cancer is globally the second most commonly diagnosed cancer type in men.Recent studies suggest that mutations in DNA repair genes are associated with aggressive forms ofprostate cancer and castration resistance. Prostate cancer with DNA repair defects may bevulnerable to therapeutic targeting by Poly(ADP‐ribose) polymerase (PARP) inhibitors. PARPenzymes modify target proteins with ADP‐ribose in a process called PARylation and are inparticular involved in single strand break repair. The rationale behind the clinical trials that led tothe current use of PARP inhibitors to treat cancer was to target the dependence of BRCA‐mutantcancer cells on the PARP‐associated repair pathway due to deficiency in homologousrecombination. However, recent studies have proposed therapeutic potential for PARP inhibitorsin tumors with a variety of vulnerabilities generating dependence on PARP beyond the syntheticlethal targeting of BRCA1/BRCA2 mutated tumors, suggesting a wider potential than initiallythought. Importantly, PARP‐associated DNA repair pathways are also closely connected toandrogen receptor (AR) signaling, which is a key regulator of tumor growth and a centraltherapeutic target in prostate cancer. In this review, we provide an extensive overview of publishedand ongoing trials exploring PARP inhibitors in treatment of prostate cancer and discuss theunderlying biology. Several clinical trials are currently studying PARP inhibitor mono‐andcombination therapies in the treatment of prostate cancer. Integration of drugs targeting DNArepair pathways in prostate cancer treatment modalities allows developing of more personalizedcare taking also into account the genetic makeup of individual tumors.

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Identifying androgen receptor (AR) and genomic characteristics that define populations of patients with mHSPC who benefit from early PARP inhibition therapy with talazoparib.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps5097 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS5097-TPS5097

Author(s):

Saro Kasparian ◽

Leanne Burnham ◽

Rick Kittles ◽

Zj Sun ◽

Fornati Bedell ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

African American ◽

Parp Inhibitor ◽

Objective Response ◽

Unmet Need ◽

Cag Repeats ◽

Parp Inhibition ◽

Castration Resistance ◽

Cellular Mechanisms

TPS5097 Background: A minority of men with mCRPC, those with DNA repair mutations, can benefit from PARP inhibitor therapy. In addition to DNA repair, PARP is used by cancer cells to interact with other cellular mechanisms including androgen receptors (AR). The next generation PARP inhibitor talazoparib can, in addition to inhibiting DNA repair, trap PARP, preventing it from carrying out its other functions. As progression in mHSPC is based on AR escape mechanisms, we predict that early exposure to PARP inhibition will delay progression. In addition, AR characteristics and function vary by ethnic populations. AR expression is inversely related with the number of polymorphic CAG repeats. As African American (AfrAm) men commonly have shorter CAG repeats in their AR, they may experience different response duration, but have been under-represented in clinical trials. Furthermore, CAG repeats may be associated with greater signaling through pathways such as wnt and Myc, which is associated with aggressive disease. Thus, studying intensified up-front therapy in a diverse prostate cancer population is a critical unmet need. Methods: 70 subjects will be treated with ADT + abiraterone + talazoparib. Outreach by our Division of Health Equities and accrual at community satellites located near diverse populations will be enlisted to accrue a target of 30% African American. Talazoparib will be dosed at 1mg daily (0.75 mg in renal insufficiency). LHRH and abiraterone formulations will be left to physician’s choice. PSA and safety labs will be checked every 4 weeks for the first 12 weeks. Imaging will be performed every 12 weeks for the first year then every 24 weeks if PSA is decreasing, or 12 weeks if rising. Data safety monitoring for toxicity after every 10 subjects have been accrued. Diversity of accrual will be evaluated after 30 subjects are enrolled; amendments will be made if the diversity goal is not achieved. Tissue genomics and ctDNA will be measured at baseline; ctDNA will be repeated after 4 weeks and at castration resistance. Endpoints: Primary: PSA nadir at 7 months has been found to be associated with overall survival and is achieved by 55% of men with mHSPC with ADT + abiraterone. With 70 subjects there is 97% power to confirm improved nadir rate of 75%, and 83% power to determine a nadir rate >70%. Secondary endpoints include objective response by RECIST 1.1 for subjects with measurable disease. radiographic progression free survival. Correlative objectives include comparing outcomes in subsets of men with high vs low number of AR CAG repeats, men with genomic alterations, and the change in ctDNA alteration fractions from baseline to 4 weeks and at progression. Progress: The trial is open to accrual as of Feb 2021. Sponsor: Pfizer/ Prostate Cancer Foundation RFP Clinical trial information: NCT04734730.

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Evaluation of the Efficacy of PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis

Frontiers in Pharmacology ◽

10.3389/fphar.2021.777663 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kan Wu ◽

Jiayu Liang ◽

Yanxiang Shao ◽

Sanchao Xiong ◽

Shuyang Feng ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Trials ◽

Meta Analysis ◽

Parp Inhibitor ◽

Objective Response ◽

Parp Inhibitors ◽

Cochrane Central Register ◽

Castration Resistant Prostate Cancer ◽

Effective Treatment Option ◽

Castration Resistant

Background: Poly(ADP-ribose) polymerase (PARP) inhibitors have breakthrough designations for metastatic castration-resistant prostate cancer (mCRPC). We performed a meta-analysis of current clinical trials to evaluate the efficacy of PARP inhibitors in mCRPC patients based on their genetic status.Methods: On August 2020, PubMed, Scopus, Embase, Cochrane Central Register of Controlled Trials, and Web of Science were searched for phase II/III clinical studies on PARP inhibitors in mCRPC patients. Data were extracted independently by two investigators and analyzed using Review Manager software version 5.3. Primary endpoints included overall response rate (ORR) and progression-free survival (PFS).Results: Nine clinical trials were identified and analyzed for the clinical benefit of PARP inhibitors in mCRPC patients (n = 1,219). Pooled analyses demonstrated that PARP inhibitors could provide a significant improvement of ORR and PFS in patients with homologous recombination deficiency (HRD) when compared with non-HRD patients. Within the HRD subgroup, BRCA mutation patients achieved significantly higher ORR [odds ratio (OR): 9.97, 95% confidence interval (CI): 6.08–16.35] and PFS rates at 12 months (OR: 3.23, 95% CI: 1.71–6.10) when compared with BRCA wild-type patients. Furthermore, patients harboring HRD without BRCA mutations have a higher objective response after PARP inhibitor treatment compared with non-HRD patients.Conclusion: PARP inhibitor is an effective treatment option for mCRPC patients with mutations in genes related to the HR DNA repair pathway when compared with non-HRD patients. In addition to BRCA mutations, other HRD-related gene aberrations may also be used as novel biomarkers to predict the efficacy of PARP inhibitors.

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PARP Inhibitors as a Therapeutic Agent for Homologous Recombination Deficiency in Breast Cancers

Journal of Clinical Medicine ◽

10.3390/jcm8040435 ◽

2019 ◽

Vol 8 (4) ◽

pp. 435 ◽

Cited By ~ 29

Author(s):

Man Keung ◽

Yanyuan Wu ◽

Jaydutt Vadgama

Keyword(s):

Dna Repair ◽

Homologous Recombination ◽

Cancer Cells ◽

Anticancer Agents ◽

Excision Repair ◽

Parp Inhibitor ◽

Predictive Biomarkers ◽

Parp Inhibitors ◽

Homologous Recombination Deficiency ◽

Repair Pathways

Poly (ADP-ribose) polymerases (PARPs) play an important role in various cellular processes, such as replication, recombination, chromatin remodeling, and DNA repair. Emphasizing PARP’s role in facilitating DNA repair, the PARP pathway has been a target for cancer researchers in developing compounds which selectively target cancer cells and increase sensitivity of cancer cells to other anticancer agents, but which also leave normal cells unaffected. Since certain tumors (BRCA1/2 mutants) have deficient homologous recombination repair pathways, they depend on PARP-mediated base excision repair for survival. Thus, inhibition of PARP is a promising strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Although PARP inhibitor therapy has predominantly targeted BRCA-mutated cancers, this review also highlights the growing conversation around PARP inhibitor treatment for non-BRCA-mutant tumors, those which exhibit BRCAness and homologous recombination deficiency. We provide an update on the field’s progress by considering PARP inhibitor mechanisms, predictive biomarkers, and clinical trials of PARP inhibitors in development. Bringing light to these findings would provide a basis for expanding the use of PARP inhibitors beyond BRCA-mutant breast tumors.

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RDNA-06. TARGETING IDH1/2-MUTANT GLIOMAS WITH UNIQUE COMBINATIONS OF DNA REPAIR INHIBITORS

Neuro-Oncology ◽

10.1093/neuonc/noz175.866 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi208-vi208

Author(s):

Amrita Sule ◽

Ranjit Bindra

Keyword(s):

Clinical Trials ◽

Dna Repair ◽

Myeloid Leukemia ◽

Parp Inhibitors ◽

Low Grade ◽

High Fidelity ◽

Isocitrate Dehydrogenase 1 ◽

Dna Repair Inhibitors ◽

Mutant Idh1 ◽

Tumor Types

Abstract Mutations in the Isocitrate Dehydrogenase-1 and -2 (IDH1/2) genes occur in the vast majority of low-grade and secondary high-grade gliomas. These neomorphic mutations occur early on in gliomagenesis leading to the production of 2-Hydroxyglutarate (2HG). 2HG has been implicated in tumorigenesis via inhibiting α-ketoglutarate (αKG)-dependent dioxygenases. Our group recently demonstrated that the production of 2HG suppresses the high-fidelity homologous recombination (HR) DNA repair pathway, resulting in a state of “BRCAness”. We initially found that mutant IDH1/2-induced BRCAness confers exquisite sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors, a finding which now has been replicated by multiple independent laboratories. Although IDH1/2 mutations were first identified in gliomas and acute myeloid leukemia (AML) cells, multiple other tumor types have subsequently been shown to harbor these mutations. Current clinical trials are testing the efficacy of PARP inhibitors as a monotherapy, as well as in combination with other DNA repair inhibitors. Here, we demonstrate that novel combinations of DNA repair inhibitors can be utilized to synergistically target IDH1/2-mutant glioma cells. In particular, we demonstrate potent synergy with ATRi and PARPis, a finding which was validated in multiple structurally unique drugs within these classes. As this combination is active in BRCA1/2-mutant cancers, in particular after the emergence of PARPi resistance, these data suggest are consistent with an underlying HR defect in IDH1/2-mutant gliomas. These preclinical investigations will provide a blueprint for future clinical trials combining PARP and ATR inhibitors in the treatment of glioblastoma.

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DNA repair germline pathogenic mutation associations with treatment duration and family history in prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.245 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 245-245

Author(s):

James Vu ◽

Marcus Marie Moses ◽

Lahiru Ranasinghe ◽

Patrick Cotogno ◽

Charlotte Manogue ◽

...

Keyword(s):

Breast Cancer ◽

Prostate Cancer ◽

Dna Repair ◽

Family History ◽

Treatment Outcomes ◽

Treatment Duration ◽

Pathogenic Mutation ◽

Germline Mutations ◽

Cancer Type ◽

History Of

245 Background: Germline mutation testing for metastatic prostate cancer patients creates a potential opportunity to personalize targeted therapies to improve treatment outcomes. The goal of this study was to characterize cancer family history, and evaluate treatment outcomes, in mCRPC patients with DNA repair pathogenic germline alterations. Methods: A retrospective study of metastatic PCa patients at Tulane Cancer Center identified 246 patients undergoing germline testing using panels (30-80 genes) (Color.com or Inviate.com). Clinical annotations included family history, life-extending treatments, and treatment duration. Statistical analyses including chi-square and Wilcoxon Rank Sum. Results: In the 246 patients tested for germline mutations, 27 patients (11.0%) had ≥1 DNA repair germline pathogenic mutation (BRCA2 = 11, BRCA1 = 3, CHEK2 = 5, ATM = 3, NBN = 1, PMS2 = 2, MSH2 = 1, PALB2 = 1) while 219 patients (89.0%) possessed no pathogenic mutation in these genes. Patients with a DNA repair pathogenic mutation were more likely to have > 2 family members affected by cancer, regardless of cancer type or degree of relationship (p = 0.04). In the DNA repair population, 5 pathogenic patients had no family history of cancer (18.5%, n = 5). Patients were more likely to have a germline alteration if they had 1 or more first degree relatives affected with breast cancer (p = 0.00001). Median lines of life-extending treatments to date between the pathogenic and non-pathogenic population were equal at 2. There were no significant differences in treatment duration for abiraterone (p = 0.49), enzalutamide (p = 0.99), docetaxel (p = 0.28), cabazitaxel (p = 0.53), carboplatin+docetaxel (p = 0.41), or radium-223 (p = 0.59) between the two groups. Conclusions: In this study, DNA repair pathogenic germline mutations did not affect treatment durations or lines of therapy but these studies are underpowered. The relationship between a family history of breast cancer and a DNA repair pathogenic mutation has not previously been reported.

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Genetic Aberrations of DNA Repair Pathways in Prostate Cancer: Translation to the Clinic

International Journal of Molecular Sciences ◽

10.3390/ijms22189783 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9783

Author(s):

Aruni Ghose ◽

Michele Moschetta ◽

George Pappas-Gogos ◽

Matin Sheriff ◽

Stergios Boussios

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Large Scale ◽

Expression Patterns ◽

Specific Antigen ◽

Distant Metastases ◽

Parp Inhibitors ◽

High Recurrence Rate ◽

Clinical Implications ◽

Genomic Landscape

Prostate cancer (PC) is the second most common cancer in men worldwide. Due to the large-scale sequencing efforts, there is currently a better understanding of the genomic landscape of PC. The identification of defects in DNA repair genes has led to clinical studies that provide a strong rationale for developing poly (ADP-ribose) polymerase (PARP) inhibitors and DNA-damaging agents in this molecularly defined subset of patients. The identification of molecularly defined subgroups of patients has also other clinical implications; for example, we now know that carriers of breast cancer 2 (BRCA2) pathogenic sequence variants (PSVs) have increased levels of serum prostate specific antigen (PSA) at diagnosis, increased proportion of high Gleason tumors, elevated rates of nodal and distant metastases, and high recurrence rate; BRCA2 PSVs confer lower overall survival (OS). Distinct tumor PSV, methylation, and expression patterns have been identified in BRCA2 compared with non-BRCA2 mutant prostate tumors. Several DNA damage response and repair (DDR)-targeting agents are currently being evaluated either as single agents or in combination in patients with PC. In this review article, we highlight the biology and clinical implications of deleterious inherited or acquired DNA repair pathway aberrations in PC and offer an overview of new agents being developed for the treatment of PC.

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PARP Inhibitors in Ovarian Cancer: The Route to “Ithaca”

Diagnostics ◽

10.3390/diagnostics9020055 ◽

2019 ◽

Vol 9 (2) ◽

pp. 55 ◽

Cited By ~ 16

Author(s):

Boussios ◽

Karathanasi ◽

Cooke ◽

Neille ◽

Sadauskaite ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Repair ◽

Homologous Recombination ◽

Brca Mutation ◽

Parp Inhibitor ◽

Parp Inhibitors ◽

Parp Inhibition ◽

Current Evidence ◽

Repair Pathway ◽

Significant Efficacy

Poly (ADP-ribose) polymerase (PARP) inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Genomic instability characterizes high-grade serous ovarian cancer (HGSOC), with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Early studies have shown significant efficacy for PARP inhibitors in patients with germline breast related cancer antigens 1 and 2 (BRCA1/2) mutations. It has also become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this treatment. Companion homologous recombination deficiency (HRD) scores are being developed to guide the selection of patients that are most likely to benefit from PARP inhibition. The choice of which PARP inhibitor is mainly based upon the number of prior therapies and the presence of a BRCA mutation or HRD. The identification of patients most likely to benefit from PARP inhibitor therapy in view of HRD and other biomarker assessments is still challenging. The aim of this review is to describe the current evidence for PARP inhibitors in ovarian cancer, their mechanism of action, and the outstanding issues, including the rate of long-term toxicities and the evolution of resistance.

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Identification of Novel Biomarkers of Homologous Recombination Defect in DNA Repair to Predict Sensitivity of Prostate Cancer Cells to PARP-Inhibitors

International Journal of Molecular Sciences ◽

10.3390/ijms20123100 ◽

2019 ◽

Vol 20 (12) ◽

pp. 3100 ◽

Cited By ~ 8

Author(s):

Daniela Criscuolo ◽

Francesco Morra ◽

Riccardo Giannella ◽

Aniello Cerrato ◽

Angela Celetti

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Homologous Recombination ◽

Cancer Cells ◽

Synthetic Lethality ◽

Parp Inhibitors ◽

Androgen Deprivation ◽

Prostate Cancer Cells ◽

Castration Resistant ◽

Novel Biomarkers

One of the most common malignancies in men is prostate cancer, for which androgen deprivation is the standard therapy. However, prostate cancer cells become insensitive to anti-androgen treatment and proceed to a castration-resistant state with limited therapeutic options. Therefore, besides the androgen deprivation approach, novel biomarkers are urgently required for specific targeting in this deadly disease. Recently, germline or somatic mutations in the homologous recombination (HR) DNA repair genes have been identified in at least 20–25% of metastatic castration-resistant prostate cancers (mCRPC). Defects in genes involved in HR DNA repair can sensitize cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors, a class of drugs already approved by the Food and Drug Administration (FDA) for breast and ovarian cancer carrying germline mutations in BRCA1/2 genes. For advanced prostate cancer carrying Breast cancer1/2 (BRCA1/2) or ataxia telengiectasia mutated (ATM) mutations, preclinical studies and clinical trials support the use of PARP-inhibitors, which received breakthrough therapy designation by the FDA. Based on these assumptions, several trials including DNA damage response and repair (DDR) targeting have been launched and are ongoing for prostate cancer. Here, we review the state-of-the-art potential biomarkers that could be predictive of cancer cell synthetic lethality with PARP inhibitors. The identification of key molecules that are affected in prostate cancer could be assayed in future clinical studies to better stratify prostate cancer patients who might benefit from target therapy.

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MicroRNA Regulation of Androgen Receptor in Castration-Resistant Prostate Cancer: Premises, Promises, and Potentials

Current Molecular Pharmacology ◽

10.2174/1874467213666201223121850 ◽

2020 ◽

Vol 13 ◽

Author(s):

Safieh Ebrahimi ◽

Seyed Isaac Hashemy ◽

Amirhossein Sahebkar ◽

Seyed Hamid AghaeeBakhtiari

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Signaling Pathways ◽

Therapeutic Potential ◽

Splice Variants ◽

Castration Resistant Prostate Cancer ◽

Castration Resistance ◽

Contributing Factors ◽

Development Of Resistance ◽

Castration Resistant

: Prostate cancer (PCa) is the second most prevalent cancer and the fifth leading cause of cancer-related deaths among men. Androgen deprivation therapy (ADT) is the most frequently used therapeutic strategy in PCa; however, the development of resistance to ADT, known as castration-resistant prostate cancer (CRPC), continues to be a major obstacle against successful treatment of PCa. The abnormal activation of the androgen receptor (AR) signaling pathway has been found as one of the main contributing factors to the development of resistance in CRPC. Therefore, AR regulatory strategies are urgently required to combat resistance. Recently, microRNAs (miRNAs) have been found as major AR regulatory factors affecting ADT resistance. MiRNAs can target AR itself, AR-related genes, AR splice variants, ARrelated signaling pathways as well as cancer stem cells (CSCs), and play critical roles in regulating ADT resistance. Due to their capability to affect various genes and signaling pathways, miRNAs are now being studied for their potential role as a new therapeutic target in CRPC. It has been recommended that combination therapies including miRNAs and existing drugs can synergistically decrease castration resistance. miRNAs have also prognostic values for ADT, and their expression profiling in CRPC patients before therapeutic scheduling may enable the physician to diagnose patients who are ADT-resistant. Overall, extant evidence obviously supports the predictive and therapeutic potential of miRNAs in CRPC patients. This review summarizes the available information about the microRNA-mediated AR controlling mechanisms involved in ADT resistance.

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Impact of germline DNA-repair gene BRCA2 and CHEK2 mutations on time to castration resistance in patients with metastatic hormone-naïve prostate cancer: A single center analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.5056 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 5056-5056

Author(s):

Vsevolod Borisovich Matveev ◽

Liudmila Lyubchenko ◽

Andrey Kirichek

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Median Time ◽

Germline Mutations ◽

Castration Resistance ◽

First Line ◽

Chek2 Mutation ◽

Mutation Carriers ◽

Significant Difference ◽

The Impact

5056 Background: Germline mutations in DNA repair genes are common in patients with andvanced and metastatic prostate cancer (mPCa). Although BRCA mutation carriers have worse outcomes than noncarriers when conventionally treated for local or locally advanced PCa, recent studies reported conflicting results regarding their aggressiveness in patients with advanced disease. This study aimed to examine the impact of germline BRCA1/2 and CHEK2 mutations on time to castration-resistance in patients with mPCa, receiving hormonal androgen deprivation therapy (ADT). Methods: A total of 76 patients with hormone-naive mPCa treated with first line ADT by luteinizing hormone-releasing hormone analogue (LHRHa) between 2014 and 2017 were recruited. Median follow-up was 34,8 mo. We focused on age, volume of metastatic spread, histologic grade, family history. All patients were genotyped for germline mutations in the BRCA1, BRCA2 and CHEK2 genes by polymerase chain reaction real-time and the Sanger sequencing. We used the standard definition of castration-resistance PCa (CRPC). Median time to CRPC were estimated using the Kaplan-Meier method, generated curves were compared using the log-rank test. Cox regression analyses were used to assess the prognostic value of BRCA1/2 and CHEK2 mutations. Results: Pathogenic and likely pathogenic germline mutations in the BRCA2 and CHEK2 gene were identified in 19 (25 %) patients. No cases of BRCA1 mutations were detected. Median time to CRPC was significantly shorter in BRCA2 and CHEK2 mutation carriers (7.9 mo, 95 % confidence interval (CI) 2.6 – 13.3), than in non-carriers (48.7 mo, 95 % CI 31.1 – 68.3, p < 0,001). There was no significant difference in median time to CRPC in BRCA2 (7.9 mo, 95 % CI 0.0 - 16.3) and CHEK2 mutation carriers (6.1 mo, 95 CI 5.0 - 7.2, p = 0,448) meanwhile both were shorter than in non-carriers (p = 0.002 and < 0,001). Multivariate analysis confirmed both BRCA2 (hazard ratio [HR]: 2.63; 95 CI 1.32-5.26, p = 0.006) and CHEK2 (HR 6.66, 95 CI 2.35-18.89, p < 0.001) mutations as an independent prognostic factor for time to CRPC, particularly in mPCa with low-volume metastatis spread (HR 3.09, 95 % CI 1.36–7.05, р = 0.007 and HR 14.1, 95 % CI 3.65-54.4, p < 0.001). Conclusions: BRCA2 and CHEK2 carriers had worse outcomes (shortened time to CRPC) than noncarriers when conventionally treated for metastatic PCa by standard first-line hormone treatment with LHRHa.

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