The new approaches to the treatment of castration- resistant prostate cancer: PARP inhibitors

Prostate cancer (PC) is one of the leading causes of cancer death in the male population. Currently, the pathogenesis of prostate cancer has been studied in sufficient detail, which makes a successful radical treatment possible in most cases. However, in about 30% of patients traditional methods (e.g., radical prostatectomy, radiation therapy, androgen deprivation therapy – ADT, etc.) are ineffective, and castration- resistant (CRPC) and metastatic (mPC) types of РС are developing. Due to the advances in modern molecular oncology, various “workarounds”, genetic and epigenetic combinations, that allow РС to progress despite the absence of androgenic stimulation, are known nowadays. A personalized approach in oncology, which gradually becomes one of the standards for mCRPC therapy, allows not only to identify specific mutations, but also to select the most effective therapy for them in the most correct way. Now the most promising groups of the drugs for mCRPC treatment are poly(ADP-ribose)-polymerase (PARP) inhibitors, immune checkpoint inhibitors, and prostate- specific membrane antigen (PSMA) targeted therapy. This article attempts to summarize the current data on PARP inhibitors. The drugs of this group are especially effective for malignant neoplasms with mutations in the BRCA 1/2 genes, and successfully used in ovarian, breast and pancreatic cancer. They have been approved for the treatment of mCRPC a not so long ago. The advent of personalized companion tests has made the treatment of mCRPC more precise. Nowadays studies on the effectiveness of PARP inhibitors for mCRPC with other genetic and epigenetic changes, as well as in combination with other therapeutic agents, are notably actual. 

1. Kaprin A.D., Starinskiy V.V., Shakhzadova O.A. (eds.). Malignant neoplasms in Russia in 2019 (morbidity and mortality). Moscow: Herzen Moscow Oncology Research Institute, a branch of the National Medical Research Radiological Center of the Ministry of Health of the Russian Federation; 2020. 252 p. (In Russ.) Available at: https://glavonco.ru/cancer_register/%D 0%97%D0%B0%D0%B1%D0%BE%D0%BB_2019_%D0%AD%D0%BB%D0% B5%D0%BA%D1%82%D1%80.pdf.

2. Scher H.I., Morris M.J., Stadler W.M., Higano C., Basch E., Fizazi K. et al. Trial design and objectives for castration- resistant prostate cancer: updated recommendations from the prostate cancer clinical trials working group 3. J Clin Oncol. 2016;34(12):1402–1418. doi: 10.1200/JCO.2015.64.2702.

3. Jun A., Zhang B., Zhang Z., Hu H., Dong J.-T. Novel Gene Signatures Predictive of Patient Recurrence‐Free Survival and Castration Resistance in Prostate Cancer. Cancers. 2021;13(4):917. doi: 10.3390/cancers13040917 .

4. Kirby M., Hirst C., Crawford E.D. Characterising the castration- resistant prostate cancer population: a systematic review. Int J Clin Pract. 2011;65(11):1180–1192. doi: 10.1111/j.1742-1241.2011.02799.x.

5. Gafanov R.A., Garmash S.V., Kravtsov I.B., Fastovets S.V. Metastatic castration- resistant prostate cancer: a current view on drug therapy and alternative tumor cell regulation. Cancer Urology. 2018;14(1):107–116. (In Russ.) doi: 10.17650/1726-9776-2018-14-1-107-116.

6. Quigley D.A., Dang H.X., Zhao S.G., Lloyd P., Aggarwal R., Alumkal J.J. et al. Genomic hallmarks and structural variation in metastatic prostate cancer. Cell. 2018;174(3):758–769.e9. doi: 10.1016/j.cell.2018.06.039.

7. Salameh A., Lee A.K., Cardó- Vila M., Nunes D.N., Efstathiou E., Staquicini F.I. et al. PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3. Proc Natl Acad Sci USA. 2015;112:8403–8408. doi: 10.1073/pnas.1507882112.

8. Zhao S.G., Chen W.S., Li H., Foye A., Zhang M., Sjöström M. et al. The DNA methylation landscape of advanced prostate cancer. Nat Genet. 2020;52(8):778–789. doi: 10.1038/s41588-020-0648-8.

9. Chung J.H., Dewal N., Sokol E., Mathew P., Whitehead R., Millis S.Z. et al. Prospective comprehensive genomic profiling of primary and metastatic prostate tumors. JCO Precis Oncol. 2019;3:PO.18.00283. doi: 10.1200/ PO.18.00283.

10. Pritchard C.C., Mateo J., Walsh M.F., De Sarkar N., Abida W., Beltran H. et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 2016;375(5):443–453. doi: 10.1056/NEJMoa1603144.

11. Davey R.A., Grossmann M. Androgen receptor structure, function and biology: From bench to bedside. Clin Biochem Rev. 2016;37(1):3–15. Available at: https://pubmed.ncbi.nlm.nih.gov/27057074/

12. Zarif J.C., Miranti C.K. The importance of non-nuclear AR signaling in prostate cancer progression and therapeutic resistance. Cell Signal. 2016;28(5): 348–356. doi: 10.1016/j.cellsig.2016.01.013.

13. Hobisch A., Eder I.E., Putz T., Horninger W., Bartsch G., Klocker H., Culig Z. Interleukin-6 regulates prostate- specific protein expression in prostate carcinoma cells by activation of the androgen receptor. Cancer Res. 1998;58(20): 4640–4645. Available at: https://pubmed.ncbi.nlm.nih.gov/9788616/

14. Ueda T., Mawji N.R., Bruchovsky N., Sadar M.D. Ligand- independent activation of the androgen receptor by interleukin-6 and the role of steroid receptor coactivator-1 in prostate cancer cells. J Biol Chem. 2002;277(41): 38087–38094. Available at: https://pubmed.ncbi.nlm.nih.gov/9788616/

15. Kim H.J., Lee W.J. Ligand- independent activation of the androgen receptor by insulin-like growth factor- I and the role of the MAPK pathway in skeletal muscle cells. Mol Cells. 2009;28(6):589–593. doi: 10.1007/s10059-009-0167-z.

16. Kim H.J., Lee W.J. Insulin-like growth factor- I induces androgen receptor activation in differentiating C2C12 skeletal muscle cells. Mol Cells. 2009;28(3):189–194. doi: 10.1007/s10059-009-0118-8.

17. Chandrasekar T., Yang J.C., Gao A.C., Evans C.P. Mechanisms of resistance in castration- resistant prostate cancer (CRPC). Transl Androl Urol. 2015;4(3):365–380. doi: 10.3978/j.issn.2223-4683.2015.05.02.

18. Maitland N.J. Resistance to Antiandrogens in Prostate Cancer: Is It Inevitable, Intrinsic or Induced? Cancers. 2021;13(2):327. doi: 10.3390/cancers13020327 .

19. Arap W., Pasqualini R., Costello J.F. Prostate Cancer Progression and the Epigenome. N Eng J Med. 2020;383(23):2287–2290. doi: 10.1056/ NEJMcibr2030475.

20. Ge R., Wang Z., Montironi R., Jiang Z., Cheng M., Santoni M. et al. Epigenetic modulations and lineage plasticity in advanced prostate cancer. Ann Oncol. 2020;31(4):470–479. doi: 10.1016/j.annonc.2020.02.002.

21. Pomerantz M.M., Qiu X., Zhu Y., Takeda D.Y., Pan W., Baca S.C. et al. Prostate cancer reactivates developmental epigenomic programs during metastatic progression. Nat Genet. 2020;52(8):790–799. doi: 10.1038/s41588-020-0664-8.

22. Waddington C.H. The strategy of the genes. London: George Allen & Unwin; 1957. doi: 10.4324/9781315765471.

23. Castro E., Romero- Laorden N., Del Pozo A., Lozano R., Medina A., Puente J. PROREPAIR-B: A Prospective Cohort Study of the Impact of Germline DNA Repair Mutations on the Outcomes of Patients With Metastatic Castration- Resistant Prostate Cancer. J Clin Oncol. 2019;37(6):490–503. doi: 10.1200/JCO.18.00358.

24. Citarelli M., Teotia S., Lamb R.S. Evolutionary history of the poly(ADP-ribose) polymerase gene family in eukaryotes. BMC Evol Biol. 2010;10(1):308. doi: 10.1186/1471-2148-10-308.

25. Dolgasheva D.S., Pevzner A.M., Ibragimova M.K., Litvyakov N.V., Tsyganov M.M. PARP1 inhibitors in breast cancer therapy. Mechanism of action and clinical use. Opukholi zhenskoy reproduktivnoy sistemy = Tumors of Female Reproductive System. 2020;16(1):55–64. (In Russ.) doi: 10.17650/1994-40982020-16-1-55-64.

26. Efremova A.S., Shram S.I., Myasoedov N.F. Doxorubicin causes transient activattion of protein poly- ADF-ribosylation in H9c2 cardiomyocytes. Doklady Akademii nauk = Reports of the Academy of Sciences. 2015;464(6):745–749. (In Russ.) doi: 10.7868/S0869565215300246.

27. Langelier M.F., Pascal J.M. PARP-1 mechanism for coupling DNA damage detection to poly-(ADP-ribose) synthesis. Curr Opin Struct Biol. 2013;23(1): 134–143. doi: 10.1016/j.sbi.2013.01.003.

28. Alkhatib H.M., Chen D., Cherney B., Bhatia K., Notario V., Giric C. et al. Cloning and expression of cDNA for human poly-(ADP-ribose) polymerase. Proc Natl Acad Sci USA. 1987;84(5):1224–1228. doi: 10.1073/pnas.84.5.1224.

29. Konecny G.E., Kristeleit R.S. PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions. Brit J Cancer. 2016;115(10):1157–1173. doi: 10.1038/bjc.2016.311.

30. Ramus S.J., Gayther S.A. The contribution of BRCA1 and BRCA2 to ovarian cancer. Mol Oncol. 2009;3(2):138–150. doi: 10.1016/j.molonc.2009.02.001.

31. Neuhausen S.L., Ozcelik H., Southey M.C., John E.M., Godwin A.K., Chung W. et al. BRCA1 and BRCA2 mutation carriers in the Breast Cancer Family Registry: an open resource for collaborative research. Breast Cancer Res Treat. 2009;116(2):379–386. doi: 10.1007/s10549-008-0153-8.

32. Tripathi A., Balakrishna P., Agarwal N. PARP inhibitors in castration- resistant prostate cancer. Cancer Treat Res Commun. 2020;24:1–3. doi: 10.1016/j. ctarc.2020.100199.

33. De Bono J.S., Mateo J., Fizazi K., Saad F., Shore N., Sandhu S. et al. Olaparib for Metastatic Castration- Resistant Prostate Cancer. N Engl J Med. 2020;382(22):2091–2102. doi: 10.1056/NEJMoa1911440.

34. Smith M.R., Saad F., Chowdhury S., Oudard S., Hadaschik B.A., Graff J.N. et al. Genitourinary tumours, prostate. Ann Oncol. 2019;30(5S):V325–V355. doi: 10.1093/annonc/mdz248.

35. De Bono J.S., Mehra N., Higano C.S., Saad F., Buttigliero C., van Oort I.M. et al. TALAPRO-1: a phase II study of talazoparib (TALA) in men with DNA damage repair mutations (DDRmut) and metastatic castration- resistant prostate cancer (mCRPC) – updated interim analysis (IA). J Clin Oncol. 2020;38(15S):5566. doi: 10.1200/JCO.2020.38.15_suppl.5566.

36. Fizazi K., Maillard A., Penel N., Baciarello G., Allouache D., Daugaard G. et al. A phase III trial of empiric chemotherapy with cisplatin and gemcitabine or systemic treatment tailored by molecular gene expression analysis in patients with carcinomas of an unknown primary (CUP) site (GEFCAPI 04). Ann Oncol. 2019;30(5S):V851–V934. doi: 10.1093/annonc/mdz394.

37. Marshall C.H., Fu W., Wang H., Baras A.S., Lotan T.L., Antonarakis E.S. Prevalence of DNA repair gene mutations in localized prostate cancer according to clinical and pathologic features: association of Gleason score and tumor stage. Prostate Cancer Prostatic Dis. 2019;22(1):59–65. doi: 10.1038/s41391-018-0086-1.

38. Mohler J.L., Antonarakis E.S. NCCN Guidelines Updates: Management of Prostate Cancer. J Natl Compr Canc Netw. 2019;17(5.5):583–586. doi: 10.6004/jnccn.2019.5011.

39. Polkinghorn W.R., Parker J.S., Lee M.X., Kass E.M., Spratt D.E., Iaquinta P.J. Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer Discov. 2013;3(11):1245–1253. doi: 10.1158/2159-8290.CD-13-0172.

40. Asim M., Tarish F., Zecchini H.I., Sanjiv K., Gelali E., Massie C.E. et al. Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer. Nat Commun. 2017;8(1):374–384. doi: 10.1038/ s41467-017-00393-y.