HRR gene mutations and characteristics of the tumor microenvironment as predictors of response to olaparib therapy in metastatic castration-resistant prostate cancer

Aim. To identify clinical, molecular, genetic, and immunological predictors of response to PARP inhibitor olaparib therapy in patients with metastatic castration-resistant prostate cancer (mCRPC) harboring germline and somatic mutations in homologous recombination repair (HRR) genes.

Materials and methods. A prospective analysis was conducted on data from 39 patients with mCRPC and HRR gene mutations (BRCA1/2, ATM, CHEK2, CDK12, among others) receiving оlaparib therapy after prior treatment with androgen receptor signaling inhibitors. Diagnoses were histologically verified according to the current WHO classification (5th edition). Genetic status was determined by next-generation sequencing (NGS). The tumor immune microenvironment was evaluated by immunohistochemical analysis assessing expression of CD4, CD8, CD68, CD163 markers and tumor-infiltrating lymphocyte (TILs) levels. Statistical analysis involved Cox proportional-hazards regression and Kaplan–Meier survival analysis.

Results. The BRCA2 mutation was the most frequently detected alteration (61 %), correlating with increased expression of CD163 and decreased CD68 expression. The most significant clinical predictors associated with improved progressionfree survival during оlaparib therapy included BRCA2 mutation positivity, patient age under 64 years, initially metastatic disease presentation, and ≥90 % reduction in prostate-specific antigen levels at 3 months post-treatment initiation. Immunological markers indicative of favorable therapeutic response included elevated levels of M2-polarized macrophages (CD163 ≥30 %) and a high CD163/CD68 ratio (≥2.83). Conversely, robust prior response to еnzalutamide therapy and administration of docetaxel during hormone-sensitive stages significantly worsened the prognosis for olaparib efficacy.

Conclusion. Olaparib therapy is effective in patients with HRRm mCRPC, with particularly effectiveness in BRCA2m tumors.  Clinical (age, disease dissemination pattern, prostate-specific antigen dynamics), immunological (CD163 expression and CD163/CD68 ratio), and molecular and genetic tumor characteristics should be considered when selecting patients for olaparib treatment, enhancing personalized therapeutic strategies in mCRPC management.

1. Mateo J., de Bono J.S., Fizazi K. et al. Olaparib for the treatment of patients with metastatic castration-resistant prostate cancer and alterations in BRCA1 and/or BRCA2 in the PROfound Trial. J Clin Oncol 2024;42(5):571–83. DOI: 10.1200/JCO.23.00339

2. Heijink A.M., Talens F., Jae L.T. et al. BRCA2 deficiency instigates cGAS-mediated inflammatory signaling and confers sensitivity to tumor necrosis factor-alpha-mediated cytotoxicity. Nat Commun 2019;10(1):100. DOI: 10.1038/s41467-018-07927-y

3. Reislander T., Lombardi E.P., Groelly F.J. et al. BRCA2 abrogation triggers innate immune responses potentiated by treatment with PARP inhibitors. Nat Commun 2019;10(1):3143. DOI: 10.1038/s41467-019-11048-5

4. Zitvogel L., Galluzzi L., Kepp O. et al. Type I interferons in anticancer immunity. Nat Rev Immunol 2015;15 (7):405–14. DOI: 10.1038/nri3845

5. Staniszewskaa A.D., Armeniaa J., Kinga M., Michalogloua C. PARP inhibition is a modulator of anti-tumor immune response in BRCA-deficient tumors. Oncoimmunology 2022;11(1):e2083755. DOI: 10.1080/2162402X.2022.2083755

6. Mustafa K., Han Y., He D. et al. Poly-(ADPribose) polymerases inhibition by Olaparib attenuates activities of the NLRP3 inflammasome and of NF-κB in THP-1 monocytes. PLoS One 2024;19(2):e0295837. DOI: 10.1371/journal.pone.0295837

7. Pandey N., Black B.E. Rapid detection and signaling of DNA damage by PARP-1. Trends Biochem Sci 2021;46:744–57. DOI: 10.1016/j.tibs.2021.01.014

8. Zong C., Zhu T., He J. et al. PARP mediated DNA damage response, genomic stability and immune responses. Int J Cancer 2022;150:1745–59. DOI: 10.1002/ijc.33918

9. Henning R.J., Bourgeois M., Harbison R.D. Poly(ADP-ribose) polymerase (PARP) and PARP inhibitors: mechanisms of action and role in cardiovascular disorders. Cardiovasc Toxicol 2018;18:493–506. DOI: 10.1007/s12012-018-9462-2

10. Hassa P.O., Hottiger M.O. The functional role of poly(ADP-ribose) polymerase 1 as novel coactivator of NF-κB in inflammatory disorders. Cell Mol Life Sci 2002;9:1534–53. DOI: 10.1007/s00018-002-8527-2

11. Dong B., Yang B., Chen W. et al. Olaparib for Chinese metastatic castration-resistant prostate cancer: a real-world study of efficacy and gene predictive analysis. Med Oncol 2022;39(5):96. DOI: 10.1007/s12032-022-01648-5

12. Ievleva A.G., Aleksakhina S.N., Sokolenko A.P. et al. Analysis of homologous recombination deficiency in prostate cancer. Sibirskiy onkologicheskiy zhurnal = Siberian Journal of Oncology 2025;24(1):59–69. (In Russ.). DOI: 10.21294/1814-4861-2025-24-1-59-69

13. Tay J.Y., Ho J.X., Cheo F.F. et al. Microenvironment and epigenetic regulation in BRCA1 pathogenic variant-associated breast cancers. Cancers 2024;16:3910. DOI: 10.3390/cancers16233910

14. Wang L., Wang D., Sonzogni O. et al. PARP-inhibition reprograms macrophages toward an anti-tumor phenotype. Cell Rep 2022;41(2):111462. DOI: 10.1016/j.celrep.2022.111462