Parp Inhibitors and Radiotherapy: A New Combination for Prostate Cancer (Systematic Review)

PARPi, in combination with ionizing radiation, has demonstrated the ability to enhance cellular radiosensitivity in different tumors. The rationale is that the exposure to radiation leads to both physical and biochemical damage to DNA, prompting cells to initiate three primary mechanisms for DNA repair. Two double-stranded DNA breaks (DSB) repair pathways: (1) non-homologous end-joining (NHEJ) and (2) homologous recombination (HR); and (3) a single-stranded DNA break (SSB) repair pathway (base excision repair, BER). In this scenario, PARPi can serve as radiosensitizers by leveraging the BER pathway. This mechanism heightens the likelihood of replication forks collapsing, consequently leading to the formation of persistent DSBs. Together, the combination of PARPi and radiotherapy is a potent oncological strategy. This combination has proven its efficacy in different tumors. However, in prostate cancer, there are only preclinical studies to support it and, recently, an ongoing clinical trial. The objective of this paper is to perform a review of the current evidence regarding the use of PARPi and radiotherapy (RT) in PCa and to give future insight on this topic.

[1]  F. Lyu,et al.  Uncovering the Secrets of Prostate Cancer’s Radiotherapy Resistance: Advances in Mechanism Research , 2023, Biomedicines.

[2]  J. Parsons,et al.  The Cellular Response to Complex DNA Damage Induced by Ionising Radiation , 2023, International journal of molecular sciences.

[3]  Rebecca A Dagg,et al.  Targeting DNA damage response pathways in cancer , 2022, Nature Reviews Cancer.

[4]  A. Vincent-Salomon,et al.  Concurrent Olaparib and Radiotherapy in Patients With Triple-Negative Breast Cancer: The Phase 1 Olaparib and Radiation Therapy for Triple-Negative Breast Cancer Trial. , 2022, JAMA oncology.

[5]  T. Zhan,et al.  Targeting the DNA Damage Response and DNA Repair Pathways to Enhance Radiosensitivity in Colorectal Cancer , 2022, Cancers.

[6]  K. Pienta,et al.  Long-Term Outcomes and Genetic Predictors of Response to Metastasis-Directed Therapy Versus Observation in Oligometastatic Prostate Cancer: Analysis of STOMP and ORIOLE Trials , 2022, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  E. H. Choi,et al.  Microwave Radiation and the Brain: Mechanisms, Current Status, and Future Prospects , 2022, International journal of molecular sciences.

[8]  M. Sydes,et al.  Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: Long-term results from the STAMPEDE randomised controlled trial , 2022, PLoS medicine.

[9]  I. Osman,et al.  PARP Inhibitors: A New Horizon for Patients with Prostate Cancer , 2022, Biomedicines.

[10]  E. Small,et al.  Phase 3 MAGNITUDE study: First results of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) as first-line therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without homologous recombination repair (HRR) gene alterations. , 2022, Journal of Clinical Oncology.

[11]  A. Armstrong,et al.  PROpel: Phase III trial of olaparib (ola) and abiraterone (abi) versus placebo (pbo) and abi as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). , 2022, Journal of Clinical Oncology.

[12]  D. Hamstra,et al.  Co-Inhibition of Androgen Receptor and PARP as a Novel Treatment Paradigm in Prostate Cancer—Where Are We Now? , 2022, Cancers.

[13]  A. Jemal,et al.  Cancer statistics, 2022 , 2022, CA: a cancer journal for clinicians.

[14]  F. Saad,et al.  Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial. , 2021, The Lancet. Oncology.

[15]  H. Fan,et al.  Ionizing Radiation Combined with PARP1 Inhibitor Reduces Radioresistance in Prostate Cancer with RB1/TP53 Loss , 2021, Cancer investigation.

[16]  M. Parmar,et al.  Association of Bone Metastatic Burden With Survival Benefit From Prostate Radiotherapy in Patients With Newly Diagnosed Metastatic Prostate Cancer , 2021, JAMA oncology.

[17]  T. H. van der Kwast,et al.  Prostate cancer , 2021, Nature Reviews Disease Primers.

[18]  J. Schellens,et al.  Phase I and Pharmacologic Study of Olaparib in Combination with High-dose Radiotherapy with and without Concurrent Cisplatin for Non–Small Cell Lung Cancer , 2020, Clinical Cancer Research.

[19]  K. O'Byrne,et al.  PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance , 2020, Frontiers in Cell and Developmental Biology.

[20]  M. Michaelson,et al.  689TiP NRG Oncology’s GU007 (NADIR): A randomized phase II trial of niraparib with standard combination androgen deprivation therapy (ADT) and radiotherapy (RT) in high-risk prostate cancer (PC) (with initial phase I) , 2020 .

[21]  C. Higano,et al.  Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration , 2020, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  O. Sartor,et al.  PARP Inhibitors & Prostate Cancer: To Infinity and Beyond BRCA. , 2020, The oncologist.

[23]  C. Parker,et al.  Prostate Cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. , 2020, Annals of oncology : official journal of the European Society for Medical Oncology.

[24]  P. Zhou,et al.  DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer , 2020, Signal Transduction and Targeted Therapy.

[25]  F. Saad,et al.  Olaparib for Metastatic Castration-Resistant Prostate Cancer. , 2020, The New England journal of medicine.

[26]  Ash A. Alizadeh,et al.  Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer , 2020, JAMA oncology.

[27]  D. Slade.  PARP and PARG inhibitors in cancer treatment. , 2020, Genes & development.

[28]  M. Hill,et al.  Radiation Track Structure: How the Spatial Distribution of Energy Deposition Drives Biological Response. , 2020, Clinical oncology (Royal College of Radiologists (Great Britain)).

[29]  Yongqing Xu,et al.  Antegrade intramedullary nail versus plate fixation in the treatment of humeral shaft fractures , 2019, Medicine.

[30]  V. Welch,et al.  Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions. , 2019, The Cochrane database of systematic reviews.

[31]  F. Saad,et al.  Pre-specified interim analysis of GALAHAD: A phase II study of niraparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD) , 2019, Annals of Oncology.

[32]  M. Sundvall,et al.  PARP Inhibitors in Prostate Cancer–the Preclinical Rationale and Current Clinical Development , 2019, Genes.

[33]  A. Tutt,et al.  A decade of clinical development of PARP inhibitors in perspective , 2019, Annals of oncology : official journal of the European Society for Medical Oncology.

[34]  Shih-Hsun Chen,et al.  Targeting dePARylation selectively suppresses DNA repair–defective and PARP inhibitor–resistant malignancies , 2019, Science Advances.

[35]  T. Schlomm,et al.  A functional ex vivo assay to detect PARP1‐EJ repair and radiosensitization by PARP‐inhibitor in prostate cancer , 2019, International journal of cancer.

[36]  S. Rottenberg,et al.  Mechanisms of PARP inhibitor resistance in cancer and insights into the DNA damage response , 2018, Genome Medicine.

[37]  C. Bokemeyer,et al.  BCL2-overexpressing prostate cancer cells rely on PARP1-dependent end-joining and are sensitive to combined PARP inhibitor and radiation therapy. , 2018, Cancer letters.

[38]  R. Simon,et al.  Loss of PTEN-assisted G2/M checkpoint impedes homologous recombination repair and enhances radio-curability and PARP inhibitor treatment response in prostate cancer , 2018, Scientific Reports.

[39]  Shih-Hsun Chen,et al.  Super-resolution imaging identifies PARP1 and the Ku complex acting as DNA double-strand break sensors , 2018, Nucleic acids research.

[40]  P. Cejka,et al.  Main steps in DNA double-strand break repair: an introduction to homologous recombination and related processes , 2018, Chromosoma.

[41]  G. Stewart,et al.  PARP1 and PARP2 stabilise replication forks at base excision repair intermediates through Fbh1-dependent Rad51 regulation , 2018, Nature Communications.

[42]  E. Goetghebeur,et al.  Surveillance or Metastasis-Directed Therapy for Oligometastatic Prostate Cancer Recurrence: A Prospective, Randomized, Multicenter Phase II Trial. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[43]  N. Oleinick,et al.  ATR/CHK1 inhibitors and cancer therapy. , 2017, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[44]  S. Tavaré,et al.  Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer , 2017, Nature Communications.

[45]  J. Habrand,et al.  Poly-(ADP-ribose)-polymerase inhibitors as radiosensitizers: a systematic review of pre-clinical and clinical human studies , 2017, Oncotarget.

[46]  S. Jackson,et al.  ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response. , 2017, Molecular cell.

[47]  M. Lieber,et al.  Non-homologous DNA end joining and alternative pathways to double-strand break repair , 2017, Nature Reviews Molecular Cell Biology.

[48]  Anne L. van de Ven,et al.  Nanoformulation of Olaparib Amplifies PARP Inhibition and Sensitizes PTEN/TP53-Deficient Prostate Cancer to Radiation , 2017, Molecular Cancer Therapeutics.

[49]  E. Yang,et al.  Poly(ADP-ribose) polymerase activity and inhibition in cancer. , 2017, Seminars in cell & developmental biology.

[50]  A. Celetti,et al.  Use of poly ADP-ribose polymerase [PARP] inhibitors in cancer cells bearing DDR defects: the rationale for their inclusion in the clinic , 2016, Journal of experimental & clinical cancer research : CR.

[51]  Y. Pommier,et al.  Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action , 2016, Science Translational Medicine.

[52]  R. Corvò,et al.  Cetuximab and Radiotherapy Versus Cisplatin and Radiotherapy for Locally Advanced Head and Neck Cancer: A Randomized Phase II Trial. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[53]  Chih-Hung Hsu,et al.  Perspectives on the combination of radiotherapy and targeted therapy with DNA repair inhibitors in the treatment of pancreatic cancer. , 2016, World journal of gastroenterology.

[54]  N. Mailand,et al.  Regulation of DNA double-strand break repair by ubiquitin and ubiquitin-like modifiers , 2016, Nature Reviews Molecular Cell Biology.

[55]  M. O’Connor,et al.  Targeting the DNA Damage Response in Cancer. , 2015, Molecular cell.

[56]  Xiaochun Yu,et al.  Poly(ADP-Ribose) Mediates the BRCA2-Dependent Early DNA Damage Response. , 2015, Cell reports.

[57]  Shih-Hsun Chen,et al.  The PIN domain of EXO1 recognizes poly(ADP-ribose) in DNA damage response , 2015, Nucleic acids research.

[58]  M. Baumann,et al.  Residual γH2AX foci after ex vivo irradiation of patient samples with known tumour-type specific differences in radio-responsiveness. , 2015, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[59]  R. Bristow,et al.  In vivo studies of the PARP inhibitor, AZD-2281, in combination with fractionated radiotherapy: An exploration of the therapeutic ratio. , 2015, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[60]  Kai Rothkamm,et al.  DNA damage foci: Meaning and significance , 2015, Environmental and molecular mutagenesis.

[61]  Lawrence D. True,et al.  Integrative Clinical Genomics of Advanced Prostate Cancer , 2015, Cell.

[62]  H. Xu,et al.  Androgen receptor: structure, role in prostate cancer and drug discovery , 2014, Acta Pharmacologica Sinica.

[63]  David J Brenner,et al.  The tumor radiobiology of SRS and SBRT: are more than the 5 Rs involved? , 2014, International journal of radiation oncology, biology, physics.

[64]  K. Cimprich,et al.  Causes and consequences of replication stress , 2013, Nature Cell Biology.

[65]  Zhao-Qi Wang,et al.  Poly(ADP-ribose) binding to Chk1 at stalled replication forks is required for S-phase checkpoint activation , 2013, Nature Communications.

[66]  Y. Pommier,et al.  Stereospecific PARP Trapping by BMN 673 and Comparison with Olaparib and Rucaparib , 2013, Molecular Cancer Therapeutics.

[67]  N. Mailand,et al.  ATR Prohibits Replication Catastrophe by Preventing Global Exhaustion of RPA , 2013, Cell.

[68]  H. Hieronymus,et al.  Androgen receptor signaling regulates DNA repair in prostate cancers. , 2013, Cancer discovery.

[69]  F. Feng,et al.  A hormone-DNA repair circuit governs the response to genotoxic insult. , 2013, Cancer discovery.

[70]  M. Lomax,et al.  Biological consequences of radiation-induced DNA damage: relevance to radiotherapy. , 2013, Clinical oncology (Royal College of Radiologists (Great Britain)).

[71]  A. Chinnaiyan,et al.  Targeted radiosensitization of ETS fusion-positive prostate cancer through PARP1 inhibition. , 2013, Neoplasia.

[72]  M. Krause,et al.  Residual γH2AX foci predict local tumour control after radiotherapy. , 2013, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[73]  Mo Li,et al.  Function of BRCA1 in the DNA damage response is mediated by ADP-ribosylation. , 2013, Cancer cell.

[74]  M. Lopes,et al.  Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition , 2013, Nature Structural &Molecular Biology.

[75]  F. Hamdy,et al.  Mre11-dependent degradation of stalled DNA replication forks is prevented by BRCA2 and PARP1. , 2012, Cancer research.

[76]  B. Telfer,et al.  Inhibition of PARP-1 by Olaparib (AZD2281) Increases the Radiosensitivity of a Lung Tumor Xenograft , 2011, Molecular Cancer Therapeutics.

[77]  C. D’Este,et al.  Short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial. , 2011, The Lancet. Oncology.

[78]  Scott H. Kaufmann,et al.  Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells , 2011, Proceedings of the National Academy of Sciences.

[79]  S. Bhide,et al.  Pre-clinical and clinical evaluation of PARP inhibitors as tumour-specific radiosensitisers. , 2010, Cancer treatment reviews.

[80]  C. L. Cutajar,et al.  External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. , 2010, The Lancet. Oncology.

[81]  Jan Lubinski,et al.  Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[82]  A. Ashworth,et al.  Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. , 2009, The New England journal of medicine.

[83]  N. Curtin,et al.  Vasoactivity of AG014699, a Clinically Active Small Molecule Inhibitor of Poly(ADP-ribose) Polymerase: a Contributory Factor to Chemopotentiation In vivo? , 2009, Clinical Cancer Research.

[84]  M. Washburn,et al.  Poly(ADP-ribosyl)ation directs recruitment and activation of an ATP-dependent chromatin remodeler , 2009, Proceedings of the National Academy of Sciences.

[85]  V. Schreiber,et al.  Radiation-induced mitotic catastrophe in PARG-deficient cells , 2009, Journal of Cell Science.

[86]  S. Takebayashi,et al.  PARP-1 ensures regulation of replication fork progression by homologous recombination on damaged DNA , 2008, The Journal of cell biology.

[87]  A. Chalmers,et al.  Replication-dependent radiosensitization of human glioma cells by inhibition of poly(ADP-Ribose) polymerase: mechanisms and therapeutic potential. , 2008, International journal of radiation oncology, biology, physics.

[88]  J. Dahm-Daphi,et al.  Hierarchy of nonhomologous end-joining, single-strand annealing and gene conversion at site-directed DNA double-strand breaks , 2008, Nucleic acids research.

[89]  J. Masson,et al.  PARP1-dependent Kinetics of Recruitment of MRE11 and NBS1 Proteins to Multiple DNA Damage Sites* , 2008, Journal of Biological Chemistry.

[90]  C. Ménard,et al.  Androgen withdrawal in patients reduces prostate cancer hypoxia: implications for disease progression and radiation response. , 2007, Cancer research.

[91]  T. Helleday,et al.  DNA double-strand break repair: from mechanistic understanding to cancer treatment. , 2007, DNA repair.

[92]  Dudley T Goodhead,et al.  Energy deposition stochastics and track structure: what about the target? , 2006, Radiation protection dosimetry.

[93]  George Iliakis,et al.  PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways , 2006, Nucleic acids research.

[94]  T. Helleday,et al.  Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair , 2006, Nucleic acids research.

[95]  V. Schreiber,et al.  Parp‐1 protects homologous recombination from interference by Ku and Ligase IV in vertebrate cells , 2006, The EMBO journal.

[96]  C. Godon,et al.  Radiosensitization by the poly(ADP-ribose) polymerase inhibitor 4-amino-1,8-naphthalimide is specific of the S phase of the cell cycle and involves arrest of DNA synthesis , 2006, Molecular Cancer Therapeutics.

[97]  W. Kaelin.  The Concept of Synthetic Lethality in the Context of Anticancer Therapy , 2005, Nature Reviews Cancer.

[98]  Thomas Helleday,et al.  Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase , 2005, Nature.

[99]  Alan Ashworth,et al.  Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy , 2005, Nature.

[100]  T. Pawlik,et al.  Role of cell cycle in mediating sensitivity to radiotherapy. , 2004, International journal of radiation oncology, biology, physics.

[101]  Zhao-Qi Wang,et al.  Ablation of PARP-1 does not interfere with the repair of DNA double-strand breaks, but compromises the reactivation of stalled replication forks , 2004, Oncogene.

[102]  C. Simbulan-Rosenthal,et al.  PARP-1 binds E2F-1 independently of its DNA binding and catalytic domains, and acts as a novel coactivator of E2F-1-mediated transcription during re-entry of quiescent cells into S phase , 2003, Oncogene.

[103]  Mitsuko Masutani,et al.  A requirement for PARP-1 for the assembly or stability of XRCC1 nuclear foci at sites of oxidative DNA damage. , 2003, Nucleic acids research.

[104]  Kai Rothkamm,et al.  Pathways of DNA Double-Strand Break Repair during the Mammalian Cell Cycle , 2003, Molecular and Cellular Biology.

[105]  A. Yasui,et al.  Spatial and Temporal Cellular Responses to Single-Strand Breaks in Human Cells , 2003, Molecular and Cellular Biology.

[106]  M. Kastan,et al.  DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation , 2003, Nature.

[107]  J. Vonesch,et al.  Functional association of poly(ADP-ribose) polymerase with DNA polymerase alpha-primase complex: a link between DNA strand break detection and DNA replication. , 1998, Nucleic acids research.

[108]  T. Butt,et al.  Nuclear protein modification and chromatin substructure. 3. Relationship between poly(adenosine diphosphate) ribosylation and different functional forms of chromatin. , 1979, Biochemistry.

[109]  R. Uzzo,et al.  Examining the Effect of PARP-1 Inhibitors on Transcriptional Activity of Androgen Receptor in Prostate Cancer Cells. , 2023, Methods in molecular biology.

[110]  K. Rothkamm,et al.  DNA Repair. , 2016, Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer.

[111]  D. Moher,et al.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. , 2010, International journal of surgery.

[112]  M. Kastan,et al.  The ATM-dependent DNA damage signaling pathway. , 2005, Cold Spring Harbor symposia on quantitative biology.

[113]  G. Poirier,et al.  DNA replication and poly(ADP-ribosyl)ation of chromatin. , 1989, Cytobios.