Prostate Cancer and PARP Inhibitors: Progress and Challenges

Overview

Journal J Hematol Oncol

Publisher Biomed Central

Specialties Hematology
Oncology

Date 2021 Mar 30

PMID 33781305

Citations 59

Authors

Diego Teyssonneau

Henri Margot

Mathilde Cabart

Mylene Anonnay

Paul Sargos

Nam-Son Vuong

Isabelle Soubeyran

Nicolas Sevenet

Guilhem Roubaud

Affiliations

Soon will be listed here.

Abstract

Despite survival improvements achieved over the last two decades, prostate cancer remains lethal at the metastatic castration-resistant stage (mCRPC) and new therapeutic approaches are needed. Germinal and/or somatic alterations of DNA-damage response pathway genes are found in a substantial number of patients with advanced prostate cancers, mainly of poor prognosis. Such alterations induce a dependency for single strand break reparation through the poly(adenosine diphosphate-ribose) polymerase (PARP) system, providing the rationale to develop PARP inhibitors. In solid tumors, the first demonstration of an improvement in overall survival was provided by olaparib in patients with mCRPC harboring homologous recombination repair deficiencies. Although this represents a major milestone, a number of issues relating to PARP inhibitors remain. This timely review synthesizes and discusses the rationale and development of PARP inhibitors, biomarker-based approaches associated and the future challenges related to their prescription as well as patient pathways.

Citing Articles

Overcoming drug resistance in castrate-resistant prostate cancer: current mechanisms and emerging therapeutic approaches.

Khorasanchi A, Hong F, Yang Y, Singer E, Wang P, Li M Cancer Drug Resist. 2025; 8:9.

PMID: 40051495 PMC: 11883235. DOI: 10.20517/cdr.2024.173.

DRG2 levels in prostate cancer cell lines predict response to PARP inhibitor during docetaxel treatment.

Lee J, Lee W, Cho S, Park J, Kwon H, Kim J Investig Clin Urol. 2025; 66(1):56-66.

PMID: 39791585 PMC: 11729229. DOI: 10.4111/icu.20240263.

The dysregulation of PARP9 expression is linked to apoptosis and DNA damage in gastric cancer cells.

Li Y, Wang X, Liu X, Li X, Zhang J, Li Y PLoS One. 2024; 19(12):e0316476.

PMID: 39739965 PMC: 11687892. DOI: 10.1371/journal.pone.0316476.

Real-world efficacy and safety of combined first-line treatment with PARP inhibitors and novel hormonal therapy in mCRPC patients with HRR gene mutations.

Guo A, Wu C, Cao J, Zhu K, Ding S Front Genet. 2024; 15:1505163.

PMID: 39712485 PMC: 11659292. DOI: 10.3389/fgene.2024.1505163.

Update on Combination Strategies of PARP Inhibitors.

Lin Z, Wang L, Xing Z, Wang F, Cheng X Cancer Control. 2024; 31:10732748241298329.

PMID: 39500600 PMC: 11539152. DOI: 10.1177/10732748241298329.

References

Murai J, Huang S, Renaud A, Zhang Y, Ji J, Takeda S . Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther. 2013; 13(2):433-43. PMC: 3946062. DOI: 10.1158/1535-7163.MCT-13-0803. View

Parker C, Castro E, Fizazi K, Heidenreich A, Ost P, Procopio G . Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020; 31(9):1119-1134. DOI: 10.1016/j.annonc.2020.06.011. View

Hussain M, Carducci M, Slovin S, Cetnar J, Qian J, McKeegan E . Targeting DNA repair with combination veliparib (ABT-888) and temozolomide in patients with metastatic castration-resistant prostate cancer. Invest New Drugs. 2014; 32(5):904-12. PMC: 4659356. DOI: 10.1007/s10637-014-0099-0. View

Abida W, Campbell D, Patnaik A, Shapiro J, Sautois B, Vogelzang N . Non-BRCA DNA Damage Repair Gene Alterations and Response to the PARP Inhibitor Rucaparib in Metastatic Castration-Resistant Prostate Cancer: Analysis From the Phase II TRITON2 Study. Clin Cancer Res. 2020; 26(11):2487-2496. PMC: 8435354. DOI: 10.1158/1078-0432.CCR-20-0394. View

Litton J, Rugo H, Ettl J, Hurvitz S, Goncalves A, Lee K . Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med. 2018; 379(8):753-763. PMC: 10600918. DOI: 10.1056/NEJMoa1802905. View

Robinson D, Van Allen E, Wu Y, Schultz N, Lonigro R, Mosquera J . Integrative clinical genomics of advanced prostate cancer. Cell. 2015; 161(5):1215-1228. PMC: 4484602. DOI: 10.1016/j.cell.2015.05.001. View

Mijic S, Zellweger R, Chappidi N, Berti M, Jacobs K, Mutreja K . Replication fork reversal triggers fork degradation in BRCA2-defective cells. Nat Commun. 2017; 8(1):859. PMC: 5643541. DOI: 10.1038/s41467-017-01164-5. View

Lazareth H, Delanoy N, Cohen R, Boissier E, Ayari H, Combe P . Nephrotoxicity Associated With Niraparib. Am J Kidney Dis. 2020; 76(6):898-900. DOI: 10.1053/j.ajkd.2020.05.021. View

Edwards S, Evans D, Hope Q, Norman A, Barbachano Y, Bullock S . Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer. 2010; 103(6):918-24. PMC: 2948551. DOI: 10.1038/sj.bjc.6605822. View

10.

Castro E, Goh C, Olmos D, Saunders E, Leongamornlert D, Tymrakiewicz M . Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013; 31(14):1748-57. PMC: 3641696. DOI: 10.1200/JCO.2012.43.1882. View

11.

Hussain M, Daignault-Newton S, Twardowski P, Albany C, Stein M, Kunju L . Targeting Androgen Receptor and DNA Repair in Metastatic Castration-Resistant Prostate Cancer: Results From NCI 9012. J Clin Oncol. 2017; 36(10):991-999. PMC: 6075827. DOI: 10.1200/JCO.2017.75.7310. View

12.

McCormick A, Swaisland H . In vitro assessment of the roles of drug transporters in the disposition and drug-drug interaction potential of olaparib. Xenobiotica. 2016; 47(10):903-915. DOI: 10.1080/00498254.2016.1241449. View

13.

Antonarakis E, Lu C, Luber B, Liang C, Wang H, Chen Y . Germline DNA-repair Gene Mutations and Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Receiving First-line Abiraterone and Enzalutamide. Eur Urol. 2018; 74(2):218-225. PMC: 6045965. DOI: 10.1016/j.eururo.2018.01.035. View

14.

Asim M, Tarish F, Zecchini H, Sanjiv K, Gelali E, Massie C . Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer. Nat Commun. 2017; 8(1):374. PMC: 5575038. DOI: 10.1038/s41467-017-00393-y. View

15.

Na R, Zheng S, Han M, Yu H, Jiang D, Shah S . Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death. Eur Urol. 2016; 71(5):740-747. PMC: 5535082. DOI: 10.1016/j.eururo.2016.11.033. View

16.

Hussain M, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S . Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020; 383(24):2345-2357. DOI: 10.1056/NEJMoa2022485. View

17.

Fizazi K, Drake C, Beer T, Kwon E, Scher H, Gerritsen W . Final Analysis of the Ipilimumab Versus Placebo Following Radiotherapy Phase III Trial in Postdocetaxel Metastatic Castration-resistant Prostate Cancer Identifies an Excess of Long-term Survivors. Eur Urol. 2020; 78(6):822-830. PMC: 8428575. DOI: 10.1016/j.eururo.2020.07.032. View

18.

Nicolosi P, Ledet E, Yang S, Michalski S, Freschi B, OLeary E . Prevalence of Germline Variants in Prostate Cancer and Implications for Current Genetic Testing Guidelines. JAMA Oncol. 2019; 5(4):523-528. PMC: 6459112. DOI: 10.1001/jamaoncol.2018.6760. View

19.

Levi V, Jacobson E, Jacobson M . Poly(ADP-ribose) has a branched structure in vivo. J Biol Chem. 1982; 257(2):607-9. View

20.

Shen Y, Rehman F, Feng Y, Boshuizen J, Bajrami I, Elliott R . BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency. Clin Cancer Res. 2013; 19(18):5003-15. PMC: 6485449. DOI: 10.1158/1078-0432.CCR-13-1391. View