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Biomarker-driven immunotherapy for precision medicine in prostate cancer

    Arianna Ottini

    Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    ,
    Pierangela Sepe

    *Author for correspondence:

    E-mail Address: pierangela.sepe@istitutotumori.mi.it

    Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    ,
    Teresa Beninato

    Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    ,
    Mélanie Claps

    Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    ,
    Valentina Guadalupi

    Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    ,
    Elena Verzoni

    Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    ,
    Patrizia Giannatempo

    Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    ,
    Giulia Baciarello

    Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    ,
    Filippo de Braud

    Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    &
    Giuseppe Procopio

    Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    Published Online:https://doi.org/10.2217/pme-2021-0079

    Although immunotherapy has recently revolutionized standard of care in different cancer types, prostate cancer has generally failed to show dramatic responses to immune checkpoint inhibitors. As in other tumors, the goal in prostate cancer is now to target treatments more precisely on patient’s individual characteristics through precision medicine. Defects in mismatch repair, mutations in the exonuclease domain of the DNA polymerase epsilon (POLE), high tumor mutational burden and the presence of biallelic loss of CDK12 among others, are predictive biomarkers of response to immunotherapy. In the present review, we summarize the evolving landscape of immunotherapy in prostate cancer, including precision approaches and strategies to define classes of responsive patients and scale up resistance to immune checkpoint inhibitors.

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

    References

    • 1. Sung H, Ferlay J, Siegel RL et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71(3), 209–249 (2021).
    • 2. Paller CJ, Antonarakis ES. Management of biochemically recurrent prostate cancer after local therapy: evolving standards of care and new directions. Clin. Adv. Hematol. Oncol. 11(1), 14–23 (2013).
    • 3. Zhang Y, Zhang Z. The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell. Mol. Immunol. 17(8), 807–821 (2020).
    • 4. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science 359(6382), 1350–1355 (2018).
    • 5. Kantoff PW, Higano CS, Shore ND et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363(5), 411–422 (2010).
    • 6. Kwon ED, Drake CG, Scher HI et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, Phase 3 trial. Lancet Oncol. 15(7), 700–712 (2014).
    • 7. Graff JN, Alumkal JJ, Drake CG et al. Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. Oncotarget 7(33), 52810–52817 (2016).
    • 8. de Almeida DVP, Fong L, Rettig MB, Autio KA. Immune checkpoint blockade for prostate cancer: niche role or next breakthrough? Am. Soc. Clin. Oncol. Educ. Book. 40, 1–18 (2020).
    • 9. Bilusic M, Madan RA, Gulley JL. Immunotherapy of prostate cancer: facts and hopes. Clin. Cancer Res. 23(22), 6764–6770 (2017).
    • 10. Claps M, Mennitto A, Guadalupi V et al. Immune-checkpoint inhibitors and metastatic prostate cancer therapy: learning by making mistakes. Cancer Treat. Rev. 88, 102057 (2020).
    • 11. Havel JJ, Chowell D, Chan TA. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat. Rev. Cancer 19(3), 133–150 (2019).
    • 12. Antonarakis ES, Piulats JM, Gross-Goupil M et al. Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: multicohort, openlabel phase II KEYNOTE-199 study. J. Clin. Oncol. 38, 395–405 (2020). • Antitumor activity of pembrolizumab in a subset of patients with RECIST-measurable and bone-predominant metastatic castration resistant prostate cancer previously treated with docetaxel and targeted endocrine therapy.
    • 13. Sharma P, Pachynski RK, Narayan V et al. Nivolumab plus ipilimumab for metastatic castration-resistant prostate cancer: preliminary analysis of patients in the CheckMate 650 trial. Cancer Cell 38(4), 489–499.e3 (2020).
    • 14. Lee L, Ali S, Genega E, Reed D, Sokol E, Mathew P. Aggressive-variant microsatellite-stable POLE mutant prostate cancer with high mutation burden and durable response to immune checkpoint inhibitor therapy. JCO Precis. Oncol. 2, 1–8 (2018).
    • 15. Guedes LB, Antonarakis ES, Schweizer MT et al. MSH2 loss in primary prostate cancer. Clin. Cancer Res. 23(22), 6863–6874 (2017).
    • 16. Antonarakis ES. Cyclin-dependent kinase 12, immunity, and prostate Cancer. N. Engl. J. Med. 379(11), 1087–1089 (2018).
    • 17. Antonarakis ES, Shaukat F, Isaacsson Velho P et al. Clinical features and therapeutic outcomes in men with advanced prostate cancer and DNA mismatch repair gene mutations. Eur. Urol. 75(3), 378–382 (2018).
    • 18. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 144(5), 646–674 (2011). •• Additional hallmarks involved in the pathogenesis of cancers and enabling characteristics that drive tumor progression.
    • 19. Knijnenburg TA, Wang L, Zimmermann MT et al. Genomic and molecular landscape of DNA damage repair deficiency across the Cancer Genome Atlas. Cell Rep. 23(1), 239–254 (2018). • Pan-cancer analysis of DNA damage repair deficiency in cancer using integrative genomic and molecular analyses to demonstrate the prognostic utility of DNA damage repair deficiency scores.
    • 20. Roy R, Chun J, Powell SN. BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat. Rev. Cancer 12(1), 68–78 (2011).
    • 21. Stellato M, Guadalupi V, Sepe P et al. The emerging role of PARP inhibitors in prostate cancer. Expert Rev. Anticancer Ther. 20(8), 715–726 (2020).
    • 22. Sishc BJ, Davis AJ. The role of the core non-homologous end joining factors in carcinogenesis and cancer. Cancers (Basel) 9(7), 81 (2017).
    • 23. Chae YK, Anker JF, Bais P, Namburi S, Giles FJ, Chuang JH. Mutations in DNA repair genes are associated with increased neo-antigen load and activated T cell infiltration in lung adenocarcinoma. Oncotarget 9(8), 7949–7960 (2017).
    • 24. Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell 163(4), 1011–1025 (2015).
    • 25. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168(4), 707–723 (2017).
    • 26. 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).
    • 27. Nombela P, Lozano R, Aytes A, Mateo J, Olmos D, Castro E. BRCA2 and other DDR genes in prostate cancer. Cancers (Basel) 11(3), 352 (2019).
    • 28. Lozano R, Castro E, Aragón IM et al. Genetic aberrations in DNA repair pathways: a cornerstone of precision oncology in prostate cancer. Br. J. Cancer 124(3), 552–563 (2021).
    • 29. Jonsson P, Bandlamudi C, Cheng ML et al. Tumour lineage shapes BRCA-mediated phenotypes. Nature 571, 576–579 (2019).
    • 30. 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). •• Multicenter study assessing the incidence of germline mutations in genes mediating DNA-repair processes among men with metastatic prostate cancer.
    • 31. Hempelmann JA, Lockwood CM, Konnick EQ et al. Microsatellite instability in prostate cancer by PCR or next-generation sequencing. J. Immunother. Cancer 6(1), 29 (2018).
    • 32. Boyiadzis MM, Kirkwood JM, Marshall JL, Pritchard CC, Azad NS, Gulley JL. Significance and implications of FDA approval of pembrolizumab for biomarker-defined disease. J. Immunother. Cancer 6(1), 35 (2018).
    • 33. Riaz N, Morris L, Havel JJ, Makarov V, Desrichard A, Chan TA. The role of neoantigens in response to immune checkpoint blockade. Int. Immunol. 28(8), 411–419 (2016).
    • 34. Snyder A, Makarov V, Merghoub T et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371(23), 2189–2199 (2014).
    • 35. Rizvi NA, Hellmann MD, Snyder A et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348(6230), 124–128 (2015).
    • 36. Wu Z, Chen H, Luo W et al. The landscape of immune cells infiltrating in prostate cancer. Front. Oncol. 10, 517637 (2020).
    • 37. Wang L, Pan S, Zhu B, Yu Z, Wang W. Comprehensive analysis of tumour mutational burden and its clinical significance in prostate cancer. BMC Urol. 21(1), 29 (2021).
    • 38. Subudhi SK, Vence L, Zhao H et al. Neoantigen responses, immune correlates, and favorable outcomes after ipilimumab treatment of patients with prostate cancer. Sci. Transl. Med. 12(537), eaaz3577 (2020).
    • 39. McGrail DJ, Pilié PG, Rashid NU et al. High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types. Ann. Oncol. 32(5), 661–672 (2021).
    • 40. Vokes NI, Liu D, Ricciuti B et al. Harmonization of tumor mutational burden quantification and association with response to immune checkpoint blockade in non-small-cell lung cancer. JCO Precis. Oncol. 3, PO.19.00171 (2019).
    • 41. Strickler JH, Hanks BA, Khasraw M. Tumor mutational burden as a predictor of immunotherapy response: is more always better? Clin. Cancer Res. 27(5), 1236–1241 (2021).
    • 42. Goodman AM, Kato S, Bazhenova L et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol. Cancer Ther. 16(11), 2598–2608 (2017).
    • 43. Tumeh PC, Harview CL, Yearley JH et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).
    • 44. Topalian SL, Hodi FS, Brahmer JR et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366(26), 2443–2454 (2012).
    • 45. Isaacsson Velho P, Antonarakis ES. PD-1/PD-L1 pathway inhibitors in advanced prostate cancer. Expert Rev. Clin. Pharmacol. 11(5), 475–486 (2018).
    • 46. Haffner MC, Guner G, Taheri D et al. Comprehensive evaluation of programmed death ligand 1 expression in primary and metastatic prostate cancer. Am. J. Pathol. 188, 1478–1485 (2018).
    • 47. Hansen AR, Massard C, Ott PA et al. Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study. Ann. Oncol. 29, 1807–1813 (2018). • Evidence of durable objective response to pembrolizumab in a subset of patients with heavily pretreated, advanced programmed death-ligand 1-positive prostate cancer.
    • 48. Jayaprakash P, Ai M, Liu A et al. Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy. J. Clin. Invest. 128, 5137–5149 (2018).
    • 49. Fukumura D, Kloepper J, Amoozgar Z et al. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat. Rev. Clin. Oncol. 15, 325–340 (2018).
    • 50. Crusz SM, Balkwill FR. Inflammation and cancer: advances and new agents. Nat. Rev. Clin. Oncol. 12, 584–596 (2015).
    • 51. Gooden MJ, de Bock GH, Leffers N et al. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br. J. Cancer 105, 93–103 (2011).
    • 52. Fridman WH, Zitvogel L, Sautès-Fridman C et al. The immune contexture in cancer prognosis and treatment. Nat. Rev. Clin. Oncol. 14, 717–734 (2017).
    • 53. Gibney GT, Weiner LM, Atkins MB. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol. 17, e542–e551 (2016). •• Exploring tumor-infiltrating lymphocytes, tumor mutation burden, immune gene signatures and multiplex immunohistochemistry to assess predictive biomarker for checkpoint inhibitor-based immunotherapy.
    • 54. Miller AM, Lundberg K, Ozenci V et al. CD4+CD25high T cells are enriched in the tumor and peripheral blood of prostate cancer patients. J. Immunol. 177, 7398–7405 (2006).
    • 55. Kiniwa Y, Miyahara Y, Wang HY et al. CD8+ Foxp3+ regulatory T cells mediate immunosuppression in prostate cancer. Clin. Cancer Res. 13, 6947–6958 (2007).
    • 56. Zhao SG, Lehrer J, Chang SL et al. The immune landscape of prostate cancer and nomination of PD-l2 as a potential therapeutic target. J. Natl Cancer Inst. 111, 301–310 (2019).
    • 57. Lundholm M, Hagglof C, Wikberg ML et al. Secreted factors from colorectal and prostate cancer cells skew the immune response in opposite directions. Sci. Rep. 5, 15651 (2015).
    • 58. Watanabe M, Kanao K, Suzuki S et al. Abstract 3961: increased CCR4-positive regulatory T cells in biopsy specimen of poor prognosis prostate cancer. Cancer Res. 77, 3961 (2017).
    • 59. Rayner E, van Gool IC, Palles C et al. A panoply of errors: polymerase proofreading domain mutations in cancer. Nat. Rev. Cancer 16(2), 71–81 (2016).
    • 60. Xing X, Kane DP, Bulock CR et al. A recurrent cancer-associated substitution in DNA polymerase ε produces a hyperactive enzyme. Nat. Commun. 10(1), 374 (2019).
    • 61. Park VS, Pursell ZF. POLE proofreading defects: contributions to mutagenesis and cancer. DNA Repair (Amst.) 76, 50–59 (2019).
    • 62. Wang F, Zhao Q, Wang YN et al. Evaluation of POLE and POLD1 mutations as biomarkers for immunotherapy outcomes across multiple cancer types. JAMA Oncol. 5(10), 1504–1506 (2019).
    • 63. Rousseau BJ, Bieche I, Pasmant E et al. 526O – high activity of nivolumab in patients with pathogenic exonucleasic domain POLE (edPOLE) mutated Mismatch Repair proficient (MMRp) advanced tumours. Ann. Oncol. 31(Suppl. 4), S462–S504 (2020).
    • 64. Blazek D, Kohoutek J, Bartholomeeusen K et al. The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes. Genes Dev. 25(20), 2158–2172 (2011).
    • 65. Barrero M, Rediti M, Crespo M et al. Tumor-infiltrating lymphocytes in biallelic-CDK12 mutated prostate cancer. J. Clin. Oncol. 36(Suppl. 15), 5070 (2018).
    • 66. Wu YM, Cieślik M, Lonigro RJ et al. Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer. Cell 173(7), 1770–1782.e14 (2018).
    • 67. Antonarakis ES, Velho PI, Fu W et al. CDK12-altered prostate cancer: clinical features and therapeutic outcomes to standard systemic therapies, poly (ADP-ribose) polymerase inhibitors, and PD-1 inhibitors. JCO Precis. Oncol. (4), 370–381 (2020).
    • 68. Nagarsheth N, Wicha MS, Zou W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat. Rev. Immunol. 17(9), 559–572 (2017).
    • 69. Reimers MA, Yip SM, Zhang L et al. Clinical outcomes in cyclin-dependent kinase 12 mutant advanced prostate cancer. Eur. Urol. 77(3), 333–341 (2020).
    • 70. Hurwitz AA, Foster BA, Kwon ED et al. Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade. Cancer Res. 60(9), 2444–2448 (2000).
    • 71. Slovin SF, Higano CS, Hamid O et al. Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter Phase I/II study. Ann. Oncol. 24(7), 1813–1821 (2013).
    • 72. Beer TM, Kwon ED, Drake CG et al. Randomized, double-blind, phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer. J. Clin. Oncol. 35(1), 40–47 (2017).
    • 73. Petrylak DP, Loriot Y, Shaffer DR et al. Safety and clinical activity of atezolizumab in patients with metastatic castration-resistant prostate cancer: a Phase I study. Clin. Cancer Res. 27(12), 3360–3369 (2021).
    • 74. Heery CR, O'Sullivan-Coyne G, Madan RA et al. Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a Phase 1a, multicohort, dose-escalation trial. Lancet Oncol. 18(5), 587–598 (2017).
    • 75. Karzai F, Madan RA, Owens et al. A Phase 2 study of olaparib and durvalumab in metastatic castrate-resistant prostate cancer (mCRPC) in an unselected population. J. Clin. Oncol. 36(6), 163 (2018).
    • 76. Karzai F, VanderWeele 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).
    • 77. Appleman LJ, Kolinsky MP, Berry WR et al. KEYNOTE-365 cohort B: pembrolizumab (pembro) plus docetaxel and prednisone in abiraterone (abi) or enzalutamide (enza)–pretreated patients with metastatic castration-resistant prostate cancer (mCRPC)—new data after an additional 1 year of follow-up. J. Clin. Oncol. 39(Suppl. 6), 10 (2021).
    • 78. Fizazi K, González Mella P, Castellano D et al. CheckMate 9KD arm B final analysis: efficacy and safety of nivolumab plus docetaxel for chemotherapy-naïve metastatic castration-resistant prostate cancer. J. Clin. Oncol. 39(Suppl. 6), 12 (2021).
    • 79. Sitkovsky MV, Hatfield S, Abbott R et al. Hostile, hypoxia-A2-adenosinergic tumor biology as the next barrier to overcome for tumor immunologists. Cancer Immunol. Res. 2, 598–605 (2014).
    • 80. Li J, Wang L, Chen X et al. CD39/CD73 upregulation on myeloid-derived suppressor cells via TGF-β-mTOR-HIF-1 signaling in patients with non–small cell lung cancer. Oncoimmunology 6, e1320011 (2017).
    • 81. Leone RD, Emens LA. Targeting adenosine for cancer immunotherapy. J. Immunother. Cancer 6, 57 (2018).
    • 82. Bendell J, Bauer T, Patel M et al. Evidence of immune activation in the first-in-human Phase Ia dose escalation study of the adenosine 2a receptor antagonist, AZD4635, in patients with advanced solid tumors. Presented at: AACR Annual Meeting 2019. GA, USA (29 March-3 April 2019).
    • 83. Porter DL, Levine BL, Kalos M et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725–733 (2011).
    • 84. Porter DL, Hwang W-T, Frey NV et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci. Transl. Med. 7, 303ra139 (2015).
    • 85. Maude SL, Frey N, Shaw PA et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).
    • 86. Ribas A. Adaptive immune resistance: how cancer protects from immune attack. Cancer Discov. 5(9), 915–919 (2015).
    • 87. Restifo NP, Smyth MJ, Snyder A. Acquired resistance to immunotherapy and future challenges. Nat. Rev. Cancer 16(2), 121–126 (2016).
    • 88. McGray AJR, Bramson J. Adaptive resistance to cancer immunotherapy. Adv. Exp. Med. Biol. 1036, 213–227 (2017).
    • 89. Gubin MM, Zhang X, Schuster H et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515(7528), 577–581 (2014).
    • 90. Chowdhury PS, Chamoto K, Honjo T. Combination therapy strategies for improving PD-1 blockade efficacy: a new era in cancer immunotherapy. J. Intern. Med. 283(2), 110–120 (2018).
    • 91. De Bono J, Mateo J, Fizazi K et al. Olaparib for metastatic castration-resistant prostate cancer. N. Engl. J. Med. 382(22), 2091–2102 (2020). •• Results from PROfound trial. Olaparib was associated with longer progression-free survival and better measures of response and patient-reported endpoints than either enzalutamide or abiraterone.
    • 92. Le DT, Uram JN, Wang H et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372(26), 2509–2520 (2015).
    • 93. NCCN Guidlines for Prostate Cancer Version 2.2021. http://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459
    • 94. Parker C, Castro E, Fizazi K et al. Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 31(9), 1119–1134 (2020).