Special Report

Genetic biomarkers to guide poly(ADP‐ribose) polymerase inhibitor precision treatment of prostate cancer

Reka Varnai

Csilla Sipeky

Reka Varnai

https://orcid.org/0000-0001-8440-3955

Department of Primary Health Care, Medical School, University of Pécs, H-7623 Pécs, Rákóczi u 2, Hungary

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Csilla Sipeky

*Author for correspondence:

E-mail Address: csilla.sipeky@gmail.com

https://orcid.org/0000-0002-8853-4722

Institute of Biomedicine & Cancer Research Laboratories, Western Cancer Centre FICAN West, University of Turku, Turku, Finland

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Published Online:6 Oct 2020https://doi.org/10.2217/pgs-2020-0019

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Abstract

Precision therapy for a subgroup of genetically defined metastatic castration-resistant prostate cancer patients may become a reality in the near future. DNA damage repair gene mutated prostate cancer might be vulnerable to treatment with PARP inhibitors (PARPi). PARPi clinical trials for prostate cancer investigate both germline and somatic genomic alterations of 43 genes for the applicability as genomic biomarker of PARPi sensitivity. Clinical trials with preliminary results show that BRCA2 and BRCA1, but also ATM, additionally BRIP1, FANCA, CDK12 and PALB2 may affect clinical end points, and may be potential candidates for genome-guided patient selection in PARPi treatment of prostate cancer.

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. NCI. Cancer stat facts: prostate cancer. https://seer.cancer.gov/statfacts/html/prost.html
Google Scholar
2. Miller KD, Nogueira L, Mariotto AB et al. Cancer treatment and survivorship statistics, 2019. CA Cancer J. Clin. 69(5), 363–385 (2019).
MedlineGoogle Scholar
3. Sartor O. Advanced prostate cancer update 2018. Asia Pac. J. Clin. Oncol. 14(Suppl. 5), 9–12 (2018).
MedlineGoogle Scholar
4. Parker C, Gillessen S, Heidenreich A, Horwich A, Committee EG. Cancer of the prostate: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 26(Suppl. 5), v69–77 (2015).
MedlineGoogle Scholar
5. de Bono JS, Logothetis CJ, Molina A et al. Abiraterone and increased survival in metastatic prostate cancer. N. Engl. J. Med. 364(21), 1995–2005 (2011).
Medline CASGoogle Scholar
6. Satoh MS, Lindahl T. Role of poly(ADP-ribose) formation in DNA repair. Nature 356(6367), 356–358 (1992).
Medline CASGoogle Scholar
7. Ray Chaudhuri A, Nussenzweig A. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat. Rev. Mol. Cell Biol. 18(10), 610–621 (2017).
MedlineGoogle Scholar
8. Brown JS, O'Carrigan B, Jackson SP, Yap TA. Targeting DNA repair in cancer: beyond PARP inhibitors. Cancer Discov 7(1), 20–37 (2017).
Medline CASGoogle Scholar
9. Castro E, Goh C, Olmos D et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J. Clin. Oncol. 31(14), 1748–1757 (2013).
Medline CASGoogle Scholar
10. Petrovics G, Price DK, Lou H et al. Increased frequency of germline BRCA2 mutations associates with prostate cancer metastasis in a racially diverse patient population. Prostate Cancer Prostatic Dis. 22, 406–410 (2018).
MedlineGoogle Scholar
11. Grasso CS, Wu YM, Robinson DR et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 487(7406), 239–243 (2012). • High priority study on genomics of advanced prostate cancer.
Medline CASGoogle Scholar
12. Pritchard CC, Mateo J, Walsh MF et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N. Engl. J. Med. 375(5), 443–453 (2016).
Medline CASGoogle Scholar
13. Robinson D, van Allen EM, Wu YM et al. Integrative clinical genomics of advanced prostate cancer. Cell 161(5), 1215–1228 (2015).
Medline CASGoogle Scholar
14. Castro E, Eeles R. The role of BRCA1 and BRCA2 in prostate cancer. Asian J. Androl. 14(3), 409–414 (2012).
Medline CASGoogle Scholar
15. Farmer H, McCabe N, Lord CJ et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434(7035), 917–921 (2005). • Describes the clinical application of synthetic lethality concept.
Medline CASGoogle Scholar
16. Bryant HE, Schultz N, Thomas HD et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434(7035), 913–917 (2005).
Medline CASGoogle Scholar
17. Lord CJ, Ashworth A. PARP inhibitors: synthetic lethality in the clinic. Science 355(6330), 1152–1158 (2017).
Medline CASGoogle Scholar
18. Brönimann S, Lemberger U, Bruchbacher A, Shariat SF, Hassler MR. Poly(ADP-ribose) polymerase inhibitors in prostate and urothelial cancer. Curr. Opin. Urol. 30(4), 519–526 (2020). •• Overview of PARP inhibitor (PARPi) trials in prostate cancer.
MedlineGoogle Scholar
19. Mateo J, Carreira S, Sandhu S et al. DNA-repair defects and olaparib in metastatic prostate cancer. N. Engl. J. Med. 373(18), 1697–1708 (2015).
Medline CASGoogle Scholar
20. Mateo J, Porta N, Bianchini D et al. Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, Phase II trial. Lancet Oncol. 21(1), 162–174 (2020). •• First prospective clinical trial in genomically defined population of patients with metastatic castration-resistant prostate cancer (mCRPC) to qualify predictive biomarkers during olaparib treatment.
Medline CASGoogle Scholar
21. Antonarakis ES, Wang H, Teply BA et al. Interim results from a Phase II study of olaparib (without ADT) in men with biochemically-recurrent prostate cancer after prostatectomy, with integrated biomarker analysis. J. Clin. Oncol. 5045–5045 (2019).
Google Scholar
22. Clarke N, Wiechno P, Alekseev B et al. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, Phase II trial. Lancet Oncol. 19(7), 975–986 (2018).
Medline CASGoogle Scholar
23. Hussain M, Mateo J, Fizazi K et al. PROfound: Phase III study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations. In: ESMO. Annals of Oncology, v851–v934 (2019).
Google Scholar
24. Wills S, Hochmuth LK, Bauer KS, Deshmukh R. Durvalumab: a newly approved checkpoint inhibitor for the treatment of urothelial carcinoma. Curr. Probl. Cancer 43(3), 181–194 (2019).
MedlineGoogle Scholar
25. Karzai F, Van der Weele D, Madan RA et al. Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations. J. Immunother. Cancer 6(1), 141 (2018).
MedlineGoogle Scholar
26. Smith MR, Sandhu SK, Kelly WK et al. Phase II study of niraparib in patients with metastatic castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD): Preliminary results of GALAHAD. J. Clin. Oncol. (Suppl. 7), 202 (2019).
MedlineGoogle Scholar
27. Abida W, Bryce AH, Vogelzang NJ et al. Preliminary results from TRITON2: a Phase II study of rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination repair (HRR) gene alterations. ESMO 29(Suppl. 8), VIII272 (2018).
Google Scholar
28. Agarwal N, Shore ND, Dunshee C et al. TALAPRO-2: a two-part, placebo-controlled Phase III study of talazoparib (TALA) with enzalutamide (ENZA) in metastatic castration-resistant prostate cancer (mCRPC). J. Clin. Oncol. (Suppl. 15), 5076 (2019).
Google Scholar
29. Hussain M, Daignault-Newton S, Twardowski PW et al. Targeting androgen receptor and DNA repair in metastatic castration-resistant prostate cancer: results from NCI 9012. J. Clin. Oncol. 36(10), 991–999 (2018).
Medline CASGoogle Scholar
30. Medinger M, Esser N, Zirrgiebel U, Ryan A, Jürgensmeier JM, Drevs J. Antitumor and antiangiogenic activity of cediranib in a preclinical model of renal cell carcinoma. Anticancer Res. 29(12), 5065–5076 (2009).
Medline CASGoogle Scholar
31. Castro E, Romero-Laorden N, Del Pozo A et al. 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. 37(6), 490–503 (2019).
Medline CASGoogle Scholar
32. Marshall CH, Sokolova AO, McNatty AL et al. Differential response to olaparib treatment among men with metastatic castration-resistant prostate cancer harboring BRCA1 or BRCA2 versus ATM mutations. Eur. Urol. 76(4), 452–458 (2019).
Medline CASGoogle Scholar
33. Chung JH, Dewal N, Sokol E et al. Prospective comprehensive genomic profiling of primary and metastatic prostate tumors. JCO Precis. Oncol. 1–31 (2019).
Google Scholar
34. Maureen O'Donnell JA, David M. Euhus. The Breast (5th Edition). Elsevier, Amsterdam, The Netherlands (2018).
Google Scholar
35. GeneCards: The Human Gene Database. Weizmann Institute of Science, London, England (2019). http://www.genecards.com
Google Scholar
36. Krajewska M, Dries R, Grassetti AV et al. CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation. Nat. Commun. 10(1), 1757 (2019).
MedlineGoogle Scholar
37. Evans MK, Longo DL. PALB2 mutations and breast-cancer risk. N. Engl. J. Med. 371(6), 566–568 (2014).
Medline CASGoogle Scholar
38. Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A. Liquid biopsy: monitoring cancer-genetics in the blood. Nat. Rev. Clin. Oncol. 10(8), 472–484 (2013). •• This review summarizes the critical clinical data as well as ongoing clinical trials for developing PARPi in treating mCRPC.
Medline CASGoogle Scholar
39. Diaz LA, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J. Clin. Oncol. 32(6), 579–586 (2014).
MedlineGoogle Scholar
40. Adashek JJ, Jain RK, Zhang J. Clinical development of PARP inhibitors in treating metastatic castration-resistant prostate cancer. Cells 8(8), 1–12 (2019).
Google Scholar

Vol. 21, No. 15

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History

Received 6 February 2020

Accepted 7 July 2020

Published online 6 October 2020

Published in print October 2020

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Acknowledgments

We thank all the technical and financial support of our institutes.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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