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Refining Immuno-Oncology Approaches in Metastatic Prostate Cancer: Transcending Current Limitations

  • Genitourinary Cancers (S Gupta, Section Editor
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Opinion statement

Due to its immunosuppressive tumor microenvironment, prostate cancer has historically been difficult to treat with immuno-oncology approaches. Other than pembrolizumab, which is now regulatory-approved for all microsatellite instability (MSI)-high and tumor mutational burden (TMB)-high advanced solid tumors, sipuleucel-T is the only immunotherapeutic agent approved by the US Food and Drug Administration (FDA) for prostate cancer. However, sipuleucel-T efficacy is optimal for select patients with indolent metastatic castration-resistant prostate cancer. Although manipulation of immune regulation by blocking immune checkpoints has led to substantial benefit in many cancers, experience with single-agent CTLA-4 and PD-1 or PD-L1 antibodies has shown limited effect for the majority of patients with prostate cancer, especially when administered as monotherapy. Combination therapies are now being attempted, in addition to enrichment strategies employing patient clinicopathologic and biologic characteristics that may heighten responses to immuno-oncology treatment, such as PD-L1 expression, TMB, MSI status, and alterations in CDK12. More work is needed to overcome the immune-exclusive barriers in prostate cancer, such as relatively low TMB, increased activity of myeloid-derived suppressor cells (MDSCs) and regulatory T cells, and defects in major histocompatibility complex (MHC) class I expression and interferon (IFN)-1 signaling. A promising approach and the likely next step in immuno-oncology for prostate cancer involves forced direction to markers expressed by prostate cancer tumor cells, such as prostate-specific membrane antigen (PSMA), that bypass the typical requirements for MHC class I interaction. The future will incorporate bispecific antibodies and chimeric antigen receptor (CAR)-T cells, potentially targeted towards phenotypic markers identified by next-generation PET imaging as part of the next wave of “precision medicine” in prostate cancer. Ultimately, we believe that the immune-exclusive prostate cancer tumor microenvironment can be overcome, and that patient outcomes can be enhanced through these more refined immuno-oncology approaches.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Fleming V, Hu X, Weber R, Nagibin V, Groth C, Altevogt P, et al. Targeting myeloid-derived suppressor cells to bypass tumor-induced immunosuppression. Front Immunol. 2018;9:398.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Vitkin N, Nersesian S, Siemens DR, Koti M. The tumor immune contexture of prostate cancer. Front Immunol. 2019;10:603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kolijn K, Verhoef EI, Smid M, Bottcher R, Jenster GW, Debets R, et al. Epithelial-mesenchymal transition in human prostate cancer demonstrates enhanced immune evasion marked by IDO1 expression. Cancer Res. 2018;78(16):4671–9.

    Article  CAS  PubMed  Google Scholar 

  5. Gunther J, Dabritz J, Wirthgen E. Limitations and off-target effects of tryptophan-related IDO inhibitors in cancer treatment. Front Immunol. 2019;10:1801.

    Article  PubMed  PubMed Central  Google Scholar 

  6. • Jha GG, Gupta S, Tagawa ST, Koopmeiners JS, Vivek S, Dudek AZ, et al. A phase II randomized, double-blind study of sipuleucel-T followed by IDO pathway inhibitor, indoximod, or placebo in the treatment of patients with metastatic castration resistant prostate cancer (mCRPC). J Clin Oncol. 2017;35(Suppl 15):3066 Phase II trial of sipuleucel-T followed by IDO inhibitor indoximod in patients with metastatic castration-resistant prostate cancer, demonstrating improvement in progression-free survival.

    Article  Google Scholar 

  7. • Lu X, Horner JW, Paul E, Shang X, Troncoso P, Deng P, et al. Effective combinatorial immunotherapy for castration-resistant prostate cancer. Nature. 2017;543(7647):728–32 Pre-clinical study using mouse model of metastatic castration-resistant prostate cancer, demonstrating synergistic inhibition with immune checkpoint inhibition combined with MDSC-targeted therapy using cabozantinib.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. • Agarwal N, Loriot Y, McGregor BA, Dreicer R, Dorff TB, Maughan BL, et al. Cabozantinib in combination with atezolizumab (A) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): results of Cohort 6 of the COSMIC-021 Study. J Clin Oncol. 2020;38(Suppl 6):139 Interim results of phase Ib COSMIC-021 trial of cabozantinib and atezolizumab in metastatic castration-resistant prostate cancer, demonstrating high response and disease control rates.

    Article  Google Scholar 

  9. •• U.S. Food and Drug Administration. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. 2017. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-first-tissuesite-agnostic-indication. Accessed 26 July 2020. FDA press release for accelerated approval granted to pembrolizumab for all MSI-high or MMR-deficient advanced solid tumors without satisfactory alternative treatment options (first tissue/site-agnostic approval).

  10. •• U.S. Food and Drug Administration. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. 2020. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adults-and-children-tmb-h-solid-tumors. Accessed 26 July 2020. FDA press release for accelerated approval granted to pembrolizumab for all TMB-high advanced solid tumors without satisfactory alternative treatment options.

  11. U.S. Food and Drug Administration. Highlights of prescribing information: Keytruda (pembrolizumab). 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125514s071s090lbl.pdf. Accessed 26 July 2020.

  12. Dendreon Pharmaceuticals LLC. Highlights of prescribing information: Provenge (sipuleucel-T). 2014. https://www.provengehcp.com/Portals/5/Provenge-PI.pdf. Accessed 26 July 2020.

  13. Madan RA, Antonarakis ES, Drake CG, Fong L, Yu EY, McNeel DG, et al. Putting the pieces together: completing the mechanism of action jigsaw for sipuleucel-T. J Natl Cancer Inst. 2020;112(6):562–73.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411–22.

    Article  CAS  PubMed  Google Scholar 

  15. Schellhammer PF, Chodak G, Whitmore JB, Sims R, Frohlich MW, Kantoff PW. Lower baseline prostate-specific antigen is associated with a greater overall survival benefit from sipuleucel-T in the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial. Urology. 2013;81(6):1297–302.

    Article  PubMed  Google Scholar 

  16. Gulley JL, Drake CG. Immunotherapy for prostate cancer: recent advances, lessons learned, and areas for further research. Clin Cancer Res. 2011;17(12):3884–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Madan RA, Gulley JL, Fojo T, Dahut WL. Therapeutic cancer vaccines in prostate cancer: the paradox of improved survival without changes in time to progression. Oncologist. 2010;15(9):979–5.

    Article  Google Scholar 

  18. Small EJ, Lance RS, Gardner TA, Karsh LI, Fong L, McCoy C, et al. A randomized phase II trial of sipuleucel-T with concurrent versus sequential abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2015;21(17):3862–9.

    Article  CAS  PubMed  Google Scholar 

  19. Petrylak DP, Drake CG, Pieczonka CM, Corman JM, Garcia JA, Dunshee C, et al. Overall survival and immune responses with sipuleucel-T and enzalutamide: STRIDE study. J Clin Oncol. 2018;36(Suppl 6):246.

    Article  Google Scholar 

  20. Fong L, Carroll P, Weinberg V, Chan S, Lewis J, Corman J, et al. Activated lymphocyte recruitment into the tumor microenvironment following preoperative sipuleucel-T for localized prostate cancer. J Natl Cancer Inst. 2014;106(11):dju268.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Wesley J, Kuan L-Y, Chadwick E, Perdue N, dela Rosa C, Frohlich M, et al. Abstract 5509: evidence of T lymphocyte activation following sipuleucel-T treatment. Cancer Res. 2011;71(Suppl 8):5509.

    Article  Google Scholar 

  22. Rekoske BT, Olson BM, McNeel DG. Antitumor vaccination of prostate cancer patients elicits PD-1/PD-L1 regulated antigen-specific immune responses. Oncoimmunology. 2016;5(6):e1165377.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Scholz M, Yep S, Chancey M, Kelly C, Chau K, Turner J, et al. Phase I clinical trial of sipuleucel-T combined with escalating doses of ipilimumab in progressive metastatic castrate-resistant prostate cancer. Immuno Targets Ther. 2017;6:11–6.

    Article  CAS  Google Scholar 

  24. Ku J, Wilenius K, Larsen C, De Guzman K, Yoshinaga S, Turner JS, et al. Survival after sipuleucel-T (SIP-T) and low-dose ipilimumab (IPI) in men with metastatic, progressive, castrate-resistant prostate cancer (M-CRPC). J Clin Oncol. 2018;36(Suppl 6):368.

    Article  Google Scholar 

  25. Raval RR, Sharabi AB, Walker AJ, Drake CG, Sharma P. Tumor immunology and cancer immunotherapy: summary of the 2013 SITC primer. J Immunother Cancer. 2014;2:14.

    Article  PubMed  PubMed Central  Google Scholar 

  26. • Marshall CH, Park JC, DeWeese TL, King S, Afful M, Hurrelbrink J, et al. Randomized phase II study of sipuleucel-T (SipT) with or without radium-223 (Ra223) in men with asymptomatic bone-metastatic castrate-resistant prostate cancer (mCRPC). J Clin Oncol. 2020;38(Suppl 6):130 Phase II trial of sipuleucel-T with radium-223 in symptomatic metastatic castration-resistant prostate cancer with bone metastases, demonstrating superior progression-free survival in the combination arm.

    Article  Google Scholar 

  27. U.S. Food and Drug Administration. Highlights of prescribing information: Yervoy (ipilimumab). 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125377s110lbl.pdf. Accessed 26 July 2020.

  28. Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations. Front Oncol. 2018;8:86.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJM, 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. 2014;15(7):700–12.

  30. •• Beer TM, Kwon ED, Drake CG, Fizazi K, Logothetis C, Gravis G, 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. 2017;35(1):40–7 Phase III trial of ipilimumab in early metastatic castration-resistant prostate cancer, demonstrating negative results.

    Article  CAS  PubMed  Google Scholar 

  31. Riley RS, June CH, Langer R, Mitchell MJ. Delivery technologies for cancer immunotherapy. Nat Rev. Drug Discov. 2019;18(3):175–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Suzman DL, Antonarakis ES. Castration-resistant prostate cancer: latest evidence and therapeutic implications. Ther Adv Med Oncol. 2014;6(4):167–79.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Fakhrejahani F, Madan RA, Dahut WL, Bilusic M, Karzai F, Cordes LM, et al. Avelumab in metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2017;35(Suppl 15):5037.

    Article  Google Scholar 

  35. Davis AA, Patel VG. The role of PD-L1 expression as a predictive biomarker: an analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors. J Immunother Cancer. 2019;7(1):278.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Ju X, Zhang H, Zhou Z, Wang Q. Regulation of PD-L1 expression in cancer and clinical implications in immunotherapy. Am J Cancer Res. 2020;10(1):1–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Hofman P. First-line immunotherapy for patients with advanced stage or metastatic non-small cell lung cancer…finally what threshold of PD-L1 expression on tumor cells? Transl Lung Cancer Res. 2019;8(5):728–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Martin AM, Nirschl TR, Nirschl CJ, Francica BJ, Kochel CM, van Bokhoven A, et al. Paucity of PD-L1 expression in prostate cancer: innate and adaptive immune resistance. Prostate Cancer Prostatic Dis. 2015;18(4):325–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gevensleben H, Dietrich D, Golletz C, Steiner S, Jung M, Thiesler T, et al. The immune checkpoint regulator PD-L1 is highly expressed in aggressive primary prostate cancer. Clin Cancer Res. 2015;22(8):1969–77.

    Article  PubMed  Google Scholar 

  40. Baas W, Gershburg S, Dynda D, Delfino K, Robinson K, Nie D, et al. Immune characterization of the programmed death receptor pathway in high risk prostate cancer. Clin Genitourin Cancer. 2017;15(5):577–81.

    Article  PubMed  Google Scholar 

  41. Calagua C, Russo J, Sun Y, Schaefer R, Lis R, Zhang Z, et al. Expression of PD-L1 in hormone-naïve and treated prostate cancer patients receiving neoadjuvant abiraterone acetate plus prednisone and leuprolide. Clin Cancer Res. 2017;23(22):6812–22.

    Article  CAS  PubMed  Google Scholar 

  42. Ness N, Anderson S, Rakaee MR, Nordbakken CV, Valkov A, Paulsen E-E, et al. The prognostic role of immune checkpoint markers programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) in a large, multicenter prostate cancer cohort. Oncotarget. 2017;8(16):26789–801.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Fankhauser CD, Schüffler PJ, Gillessen S, Omlin A, Rupp NJ, Rueschoff JH, et al. Comprehensive immunohistochemical analysis of PD-L1 shows scarce expression in castration-resistant prostate cancer. Oncotarget. 2018;9(12):10284–93.

    Article  PubMed  Google Scholar 

  44. Haffner MC, Guner G, Taheri D, Netto GJ, Palsgrove DN, Zheng Q, et al. Comprehensive evaluation of programmed death-ligand 1 expression in primary and metastatic prostate cancer. Am J Pathol. 2018;188(6):1478–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Petitprez F, Fossati N, Vano Y, Freschi M, Becht E, Luciano R, et al. PD-L1 expression and CD8+ T cell infiltrate are associated with clinical progression in patients with node-positive prostate cancer. Eur Urol Focus. 2019;5(2):192–6.

    Article  PubMed  Google Scholar 

  46. Sharma M, Yang Z, Miyamoto H. Immunohistochemistry of immune checkpoint markers PD-1 and PD-L1 in prostate cancer. Medicine (Baltimore). 2019;98(38):e17257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hansen AR, Massard C, Ott PA, Haas NB, Lopez JS, Ejadi S, et al. Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study. Ann Oncol. 2018;29(8):1807–13.

    Article  CAS  PubMed  Google Scholar 

  48. •• Antonarakis ES, Piulats JM, Gross-Goupil M, Goh J, Ojamaa K, Hoimes CJ, et al. Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: multicohort, open-label phase II KEYNOTE-199 study. J Clin Oncol. 2020;38(5):395–405 Phase II KEYNOTE-199 trial of pembrolizumab in PD-L1-positive metastatic castration-resistant prostate cancer, demonstrating limited utility of single-agent pembrolizumab.

    Article  CAS  PubMed  Google Scholar 

  49. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pritchard CC, Morrissey C, Kumar A, Zhang X, Smith C, Coleman I, et al. Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer. Nat Commun. 2014;5:4988.

    Article  CAS  PubMed  Google Scholar 

  51. Robinson D, Van Allen EM, Wu Y-M, Schultz N, Lonigro RJ, Mosquera J-M, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Schweizer MT, Cheng HH, Tretiakova MS, Vakar-Lopez F, Klemfuss N, Konnick EQ, et al. Mismatch repair deficiency may be common in ductal adenocarcinoma of the prostate. Oncotarget. 2016;7(50):82504–10.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Schweizer MT, Antonarakis ES, Bismar TA, Guedes LB, Cheng HH, Tretiakova M, et al. Genomic characterization of prostatic ductal adenocarcinoma identifies a high prevalence of DNA repair gene mutations. JCO Precis Oncol. 2019;3. https://doi.org/10.1200/PO.18.00327.

  54. Ritch E, Fu SYF, Herberts C, Wang G, Warner EW, Schonlau E, et al. Identification of hypermutation and defective mismatch repair in ctDNA from metastatic prostate cancer. Clin Cancer Res. 2020;26(5):1114–25.

    Article  CAS  PubMed  Google Scholar 

  55. Schweizer MT, Yu EY. “Matching” the “mismatch” repair–deficient prostate cancer with immunotherapy. Clin Cancer Res. 2020;26(5):981–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. •• Wu Y-M, Cieslik M, Lonigro RJ, Vats P, Reimers MA, Cao X, et al. Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer. Cell. 2018;173(7):1770–82.e14 Integrative genomic analysis of 360 metastatic castration-resistant prostate cancer samples, identifying a novel subtype characterized by biallelic loss of CDK12.

    Article  CAS  PubMed  Google Scholar 

  57. Nguyen B, Mota JM, Nandakumar S, Stopsack KH, Weg E, Rathkopf D, et al. Pan-cancer analysis of CDK12 alterations identifies a subset of prostate cancers with distinct genomic and clinical characteristics. Eur Urol. 2020;S0302–2838(20):30199–8.

    Google Scholar 

  58. Antonarakis ES, Velho PI, Fu W, Wang H, Agarwal N, Santos VS, 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. 2020;4:370–81.

    Article  PubMed  Google Scholar 

  59. Bishop JL, Sio A, Angeles A, Roberts ME, Azad AA, Chi KN, et al. PD-L1 is highly expressed in Enzalutamide resistant prostate cancer. Oncotarget. 2015;6(1):234–42.

    Article  PubMed  Google Scholar 

  60. Graff JN, Alumkal JJ, Drake CG, Thomas GV, Redmond WL, Farhad M, et al. Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. Oncotarget. 2016;7(33):52810–7.

    Article  PubMed  PubMed Central  Google Scholar 

  61. • Graff JN, Alumkal JJ, Thompson RF, Moran A, Thomas GV, Wood MA, et al. Pembrolizumab (Pembro) plus enzalutamide (Enz) in metastatic castration resistant prostate cancer (mCRPC): extended follow up. J Clin Oncol. 2018;36(Suppl 15):5047 Phase II trial of pembrolizumab and enzalutamide in patients with metastatic castration-resistant prostate cancer progressing on enzalutamide, demonstrating dramatic and durable responses in some patients.

    Article  Google Scholar 

  62. Graff JN, Antonarakis ES, Hoimes CJ, Tagawa ST, Hwang C, Kilari D, et al. Pembrolizumab (pembro) plus enzalutamide (enza) for enza-resistant metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-199 cohorts 4–5. J Clin Oncol. 2020;38(Suppl 6):15.

    Article  Google Scholar 

  63. Yu EY, Fong P, Piulats JM, Appleman L, Conter H, Feyerabend S, et al. Pembrolizumab plus enzalutamide in abiraterone-pretreated patients with metastatic castration-resistant prostate cancer: updated results from KEYNOTE-365 Cohort C. J Urol. 2020;203(Suppl 4S):e368.

    Google Scholar 

  64. Berry WR, Fong PCC, Piulats JM, Appleman LJ, Conter HJ, Feyerabend S, et al. KEYNOTE-365 cohort C updated results: pembrolizumab (pembro) plus enzalutamide (enza) in abiraterone (abi)-pretreated patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC). J Clin Oncol. 2020;38(Suppl 6):102.

    Article  Google Scholar 

  65. Graff JN, Burgents J, Liang LW, Stenzl A. KEYNOTE-641: phase 3 study of pembrolizumab (pembro) plus enzalutamide for metastatic castration-resistant prostate cancer (mCRPC). Ann Oncol. 2019;30(Suppl 5):325–55.

    Google Scholar 

  66. •• Sweeney CJ, Gillessen S, Rathkopf D, Matsubara N, Drake C, Fizazi K, et al. CT014 – Imbassador250: A phase III trial comparing atezolizumab with enzalutamide vs enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC). AACR Annual Meeting 2020: Session VCTPL01 - Opening Clinical Plenary. https://www.abstractsonline.com/pp8/#!/9045/presentation/10596. Accessed 26 July 2020. Phase III IMbassador 250 trial of enzalutamide and atezolizumab in enzalutamide-naïve patients with metastatic castration-resistant prostate cancer, which was closed for futility at interim analysis.

  67. Honey, K. AACR Virtual Annual Meeting I: the promises and challenges of expanding the use of immune checkpoint inhibitors through combination therapy. 2020. https://www.aacr.org/professionals/blog/aacr-virtual-annual-meeting-i-the-promises-and-challenges-of-expanding-the-use-of-immune-checkpoint-inhibitors-through-combination-therapy/. Accessed 26 July 2020.

  68. Mateo J, Lord CJ, Serra V, Tutt A, Balmana J, Castroviejo-Bermejo M, et al. A decade of clinical development of PARP inhibitors in perspective. Ann Oncol. 2019;30(9):1437–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. • Shen J, Zhao W, Ju Z, Wang L, Peng Y, Labrie M, et al. PARPi triggers the STING-dependent immune response and enhances the therapeutic efficacy of immune checkpoint blockade independent of BRCAness. Cancer Res. 2019;79(2):311–9 Pre-clinical study using cell lines and mouse models elucidating the mechanism involving the STING pathway behind clinical efficacy of PARP inhibitors, including a rationale for combinations with immune checkpoint blockade.

    Article  CAS  PubMed  Google Scholar 

  70. • Jiao S, Xia W, Yamaguchi H, Wei Y, Chen M-K, Hsu J-M, et al. PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression. Clin Cancer Res. 2017;23(14):3711–20 Pre-clinical study using mouse models demonstrating synergistic effect with PARP inhibition and PD-L1 blockade.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. • Karzai F, VanderWeele D, Madan RA, Owens H, Cordes LM, Hankin A, 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. 2018;6(1):141 Phase II trial of durvalumab and olaparib in heavily pretreated patients with metastatic castration-resistant prostate cancer, showing high frequency of germline or somatic DNA damage repair alterations in responders.

    Article  PubMed  PubMed Central  Google Scholar 

  72. • Yu EY, Piulats JM, Gravis G, Laguerre B, Arija JAA, Oudard S, et al. KEYNOTE-365 cohort A updated results: Pembrolizumab (pembro) plus olaparib in docetaxel-pretreated patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2020;38(Suppl 6):100 Phase II KEYNOTE-365 trial cohort A of pembrolizumab and olaparib in patients with metastatic castration-resistant prostate cancer.

    Article  Google Scholar 

  73. Yap TA, Beck JT, Stewart RA, Dahm SC, Chappey C, Cesari R, et al. Javelin PARP Medley: a phase 1b/2 study of avelumab (anti-PD-L1) plus talazoparib in locally advanced or metastatic solid tumors. Ann Oncol. 2018;29(Suppl 8):viii400–41.

    Google Scholar 

  74. Fizazi K, Drake CG, Shaffer DR, Pachynski R, Saad F, Ciprotti M, et al. An open-label, phase 2 study of nivolumab in combination with either rucaparib, docetaxel, or enzalutamide in men with castration-resistant metastatic prostate cancer (mCRPC; CheckMate 9KD). J Clin Oncol. 2018;36(Suppl 15):TPS3126.

    Article  Google Scholar 

  75. Yu EY, Park SH, Huang Y-H, Bennamoun M, Xu L, Kim J, et al. Phase III study of pembrolizumab (pembro) plus olaparib versus enzalutamide (enza) or abiraterone acetate (abi) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who progressed on chemotherapy: KEYLYNK-010. J Clin Oncol. 2020;38(Suppl 6):TPS256.

    Article  Google Scholar 

  76. Hodge JW, Garnett CT, Farsaci B, Palena C, Tsang K-Y, Ferrone S, et al. Chemotherapy-induced immunogenic modulation of tumor cells enhances killing by cytotoxic T lymphocytes and is distinct from immunogenic cell death. Int J Cancer. 2013;133(3):624–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. • Massard C, Retz M, Hammerer P, Quevedo F, Fong PCC, Berry WR, et al. Keynote-365 cohort b: Pembrolizumab (pembro) plus docetaxel and prednisone in abiraterone (abi) or enzalutamide (enza)-pretreated patients (pts) with metastatic castrate resistant prostate cancer (mCRPC). J Clin Oncol. 2019;37(Suppl 7):170 Interim results of phase II KEYNOTE-365 trial cohort B of docetaxel and pembrolizumab in metastatic castration-resistant prostate cancer.

    Article  Google Scholar 

  78. • Fizazi K, Gonzalez Mella P, Castellano D, Minatta JN, Rezazadeh Kalebasty A, Shaffer D, et al. Efficacy and safety of nivolumab in combination with docetaxel in men with metastatic castration-resistant prostate cancer in CHECKMATE 9KD. Ann Oncol. 2019;30(Suppl 5):v851–934 Interim results of phase II CheckMate 9KD trial arm of docetaxel and nivolumab in metastatic castration-resistant prostate cancer.

    Article  Google Scholar 

  79. Petrylak DP, Shore ND, Bennamoun M, Ratta R, Piulats JM, Li B, et al. Phase III study of pembrolizumab (pembro) plus docetaxel and prednisone for enzalutamide (enza)- or abiraterone acetate (abi)–pretreated patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-921. J Clin Oncol. 2020;38(Suppl 6):TPS262.

    Article  Google Scholar 

  80. Exelixis News Release. Exelixis announces initiation of CONTACT-02 phase 3 pivotal trial of cabozantinib in combination with atezolizumab in previously treated metastatic castration-resistant prostate cancer. 2020. https://ir.exelixis.com/node/21696/pdf. Accessed 26 July 2020.

  81. Yu S, Li A, Liu Q, Yuan X, Xu H, Jiao D, et al. Recent advanced of bispecific antibodies in solid tumors. J Hematol Oncol. 2017;10(1):155.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Slovin SF. Immunotherapy for castration-resistant prostate cancer: has its time arrived? Expert Opin Biol Ther. 2020;20(5):481–7.

    Article  CAS  PubMed  Google Scholar 

  83. Barroca-Ferreira J, Pais JP, Santos MM, Goncalves AM, Gomes IM, Sousa I, et al. Targeting STEAP1 protein in human cancer: current trends and future challenges. Curr Cancer Drug Targets. 2018;18(3):222–30.

    Article  CAS  PubMed  Google Scholar 

  84. Kelly WK, Danila DC, Edenfield WJ, Aggarwal RR, Petrylak DP, Sartor AO, et al. Phase I study of AMG 509, a STEAP1 x CD3 T cell-recruiting XmAb 2+1 immune therapy, in patients with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2020;38(Suppl 15):TPS5598.

    Google Scholar 

  85. Bailis J, Deegen P, Thomas O, Bogner P, Wahl J, Liao M, et al. Preclinical evaluation of AMG 160, a next-generation bispecific T cell engager (BiTE) targeting the prostate-specific membrane antigen PSMA for metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2019;37(Suppl 7):301.

    Article  Google Scholar 

  86. Tran B, Horvath L, Dorff TB, Greil R, Machiels J-PH, Roncolato F, et al. Phase I study of AMG 160, a half-life extended bispecific T cell engager (HLE BiTE) immune therapy targeting prostate-specific membrane antigen (PSMA), in patients with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2020;38(Suppl 6):TPS261.

    Article  Google Scholar 

  87. Hummel H-D, Kufer P, Grullich C, Deschler-Baier B, Chatterjee M, Goebeler M-E, et al. Phase 1 study of pasotuxizumab (BAY 2010112), a PSMA-targeting Bispecific T cell Engager (BiTE) immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2019;37(Suppl 15):5034.

    Article  Google Scholar 

  88. • Hummel H-D, Kufer P, Grullich C, Deschler-Baier B, Chatterjee M, Goebeler M-E, et al. Phase I study of pasotuxizumab (AMG 212/BAY 2010112), a PSMA-targeting BiTE (Bispecific T cell Engager) immune therapy for metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2020;38(Suppl 6):124 Phase I trial of PSMA-targeting BiTE pasotuxizumab in metastatic castration-resistant prostate cancer.

    Article  Google Scholar 

  89. Ramos CA, Dotti G. Chimeric antigen receptor (CAR)-engineered lymphocytes for cancer therapy. Expert Opin Biol Ther. 2011;11(7):855–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Carpenito C, Milone MC, Hassan R, Simonet JC, Lakhal M, Suhoski MM, et al. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci U S A. 2009;106(9):3360–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Chmielewski M, Kopecky C, Hombach AA, Abken H. IL-12 release by engineered T cells expressing chimeric antigen receptors can effectively muster an antigen-independent macrophage response on tumor cells that have shut down tumor antigen expression. Cancer Res. 2011;71(17):5697–706.

    Article  CAS  PubMed  Google Scholar 

  92. Gorchakov AA, Kulemzin SV, Kochneva GV, Taranin AV. Challenges and prospects of chimeric antigen receptor T cell therapy for metastatic prostate cancer. Eur Urol. 2019;77(3):299–308.

    Article  PubMed  Google Scholar 

  93. Dorff TB, Fanti S, Farolfi A, Reiter RE, Sadun TY, Sartor O. The evolving role of prostate-specific membrane antigen–based diagnostics and therapeutics in prostate cancer. Am Soc Clin Oncol Educ Book. 2019;39:321–30.

    Article  PubMed  Google Scholar 

  94. Gu Z, Thomas G, Yamashiro J, Shintaku IP, Dorey F, Raitano A, et al. Prostate stem cell antigen (PSCA) expression increases with high Gleason score, advanced stage and bone metastasis in prostate cancer. Oncogene. 2009;19(10):1288–96.

    Article  Google Scholar 

  95. Junghans RP, Ma Q, Rathore R, Gomes EM, Bais AJ, Lo ASY, et al. Phase I trial of anti-PSMA designer CAR-T cells in prostate cancer: possible role for interacting interleukin 2-T cell pharmacodynamics as a determinant of clinical response. Prostate. 2016;76(14):1257–70.

    Article  CAS  PubMed  Google Scholar 

  96. Slovin SF, Wang X, Hullings M, Arauz G, Bartido S, Lewis JS, et al. Chimeric antigen receptor (CAR+) modified T cells targeting prostate-specific membrane antigen (PSMA) in patients (pts) with castrate metastatic prostate cancer (CMPC). J Clin Oncol. 2013;31(Suppl 15):72.

    Article  Google Scholar 

  97. Wikström P, Stattin P, Franck-Lissbrant I, Damber JE, Bergh A. Transforming growth factor beta1 is associated with angiogenesis, metastasis, and poor clinical outcome in prostate cancer. Prostate. 1998;37(1):19–29.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Oncology, Department of Medicine, University of Washington, 825 Eastlake Ave E, G4830, Seattle, WA, 98109-1023, USA

    Risa L. Wong MD & Evan Y. Yu MD

  2. Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, D5-100, Seattle, WA, 98109-1024, USA

    Risa L. Wong MD & Evan Y. Yu MD

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Correspondence to Risa L. Wong MD.

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Conflict of Interest

Evan Y. Yu has received research funding from Bayer, Dendreon, Merck, Pharmacyclics, Seattle Genetics, Daiichi Sankyo, Taiho Pharmaceutical, and Blue Earth Diagnostics, Inc.; and has received compensation for service as a consultant from Amgen, AstraZeneca, Bayer, Clovis Oncology, Dendreon, Janssen, Merck, Pharmacyclics, Seattle Genetics, Advanced Accelerator Applications, Sanofi, AbbVie, Incyte Corporation, and QED Therapeutics. Risa L. Wong declares that she has no conflict of interest.

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Wong, R.L., Yu, E.Y. Refining Immuno-Oncology Approaches in Metastatic Prostate Cancer: Transcending Current Limitations. Curr. Treat. Options in Oncol. 22, 13 (2021). https://doi.org/10.1007/s11864-020-00808-x

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