https://doi.org/10.4081/aiua.2024.12307
The role of immunotherapy in urological cancers
Submitted: January 24, 2024
Accepted: February 10, 2024
Published: May 30, 2024
Accepted: February 10, 2024
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
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Immunotherapy is defined as a therapeutic approach that targets or manipulates the immune system. A deeper understanding of the cellular and molecular composition of the tumour environment, as well as the mechanisms controlling the immune system, has made possible the development and clinical investigation of many innovative cancer therapies. Historically, immunotherapy has played an essential role in treating urologic malignancies, while in the modern era, the development of immune checkpoint inhibitors (ICIs) has been critical to urology. Urothelial carcinoma is a common type of cancer in the genitourinary system, and treatment strategies in this area are constantly evolving. Intravesical and systemic immunotherapeutic agents have begun to be used increasingly frequently in treating urothelial carcinoma. These agents increase the anti-tumour response by affecting the body's defence mechanisms. Immunotherapeutic agents used in urothelial carcinoma include various options such as BCG, interferon, anti-PD-1 (pembrolizumab, nivolumab) and anti-PD-L1 (atezolizumab, avelumab, durvalumab). Renal cell carcinoma (RCC) has been known for many years as a tumour with unique sensitivity to immunotherapies. The recent emergence of ICIs that block PD-1/PD-L1 (pembrolizumab, nivolumab, atezolizumab) or CTLA4 (ipilimumab) signalling pathways has reestablished systemic immunotherapy as central to the treatment of advanced RCC. In light of randomized clinical trials conducted with increasing interest in the application of immunotherapies in the adjuvant setting, combination therapies (nivolumab/ipilimumab, nivolumab/cabozantinib, pembrolizumab/ axitinib, pembrolizumab/lenvantinib) have become the standard first-line treatment of metastatic RCC. Prostate cancer is in the immunologically "cold" tumour category; on the contrary, in recent years, immunotherapeutic agents have come to the fore as an essential area in the treatment of this disease. Especially in the treatment of castration-resistant prostate cancer, immunotherapeutic agents constitute an alternative treatment method besides androgen deprivation therapy and chemotherapy. Ipilimumab, nivolumab, pembrolizumab, atezolizumab, and Sipuleucel T (Vaccine-based) are promising alternative treatment options. Considering ongoing randomized clinical trials, immunotherapeutic agents promise to transform the uro-oncology field significantly. In this review, we aimed to summarize the role of immunotherapy in urothelial, renal and prostate cancer in the light of randomized clinical trials.
Elena Dreyzin AK. Kidney Cancer and Its Treatment. In: Edouard J. Trabulsi CDL, Anne E. Lizardi-Calvaresi, editor. Chemotherapy and Immunotherapy in Urologic Oncology. Switzerland: Springer Nature; 2021. p. 231-7.
Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976; 116:180-3.
Rosenberg SA, Lotze MT, Muul LM, et al. Observations on the systemic administration of autologous lymphokine activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. New Engl J Med. 1985; 313:1485-92.
Cassell A, 3rd, Manobah B, Willie S. Diagnostic and Therapeutic Challenges of Rare Urogenital Cancers: Urothelial Carcinoma of the Renal Pelvis, Ureters and Urethra. World journal of oncology. 2021; 12:20-7.
Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68:394-424.
Babjuk M, Burger M, Comperat EM, et al. European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (TaT1 and Carcinoma In Situ) - 2019 Update. Eur Urol. 2019; 76:639-57.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019; 69:7-34.
Petros FG. Epidemiology, clinical presentation, and evaluation of upper-tract urothelial carcinoma. Transl Androl Urol. 2020; 9:1794-8.
Ward Grados DF, Ahmadi H, Griffith TS, Warlick CA. Immunotherapy for Bladder Cancer: Latest Advances and Ongoing Clinical Trials. Immunol Invest. 2022; 51:2226-51.
Naitoh J, Franklin J, O'Donnell MA, Belldegrun AS. Interferon alpha for the treatment of superficial bladder cancer. Adv Exp Med Biol. 1999; 462:371-86.
Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive
bladder cancer unresponsive to BCG (KEYNOTE-057): an openlabel, single-arm, multicentre, phase 2 study. Lancet Oncol. 2021; 22:919-30.
Balar AV, Castellano D, O'Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol 2017; 18:1483-92.
Necchi A, Anichini A, Raggi D, et al. Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. J Clin Oncol 2018; 36:3353-60.
Rose TL, Harrison MR, Deal AM, et al. Phase II Study of Gemcitabine and Split-Dose Cisplatin Plus Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Bladder Cancer. J Clin Oncol. 2021; 39:3140-8.
Galsky MD, Mortazavi A, Milowsky MI, et al. Randomized Double-Blind Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer. J Clin Oncol 2020; 38:1797-806.
Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. New Engl J Med 2017; 376:1015-26.
Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017; 18:312-22.
Sharma P, Siefker-Radtke A, de Braud F, et al. Nivolumab Alone and With Ipilimumab in Previously Treated Metastatic Urothelial Carcinoma: CheckMate 032 Nivolumab 1 mg/kg Plus Ipilimumab 3 mg/kg Expansion Cohort Results. J Clin Oncol. 2019; 37:1608-16.
Rouprêt M, Seisen T, Birtle AJ, et al. European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2023 Update. Eur Urol. 2023; 84:49-64.
Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. New Engl J Med 2021; 384:2102-14.
Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016; 387:1909-20.
Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as firstline treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 2017; 389:67-76.
Funt SA, Lattanzi M, Whiting K, et al. Neoadjuvant Atezolizumab With Gemcitabine and Cisplatin in Patients With Muscle-Invasive Bladder Cancer: A Multicenter, Single-Arm, Phase II Trial. J Clin Oncol. 2022; 40:1312-22.
Galsky MD, Arija JAA, Bamias A, et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2020; 395:1547-57.
Powles T, Park SH, Voog E, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. New Engl J Med. 2020; 383:1218-30.
Erck A, Aragon-Ching JB. Maintenance avelumab for metastatic urothelial cancer: a new standard of care. Cancer Biol Ther. 2020; 21:1095-6.
Powles T, van der Heijden MS, Castellano D, et al. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, openlabel, multicentre, phase 3 trial. Lancet Oncol. 2020; 21:1574-88.
Rhea LP, Aragon-Ching JB. Advances and Controversies With Checkpoint Inhibitors in Bladder Cancer. Clin Med Insights Oncol. 2021; 15:11795549211044963.
Abd El-Salam MA, Smith CEP, Pan CX. Insights on recent innovations in bladder cancer immunotherapy. Cancer Cytopathol. 2022; 130:667-83.
Ferlay J, Colombet M, Soerjomataram I, et al. Cancer incidence and mortality patterns in Europe: Estimates for 40 countries and 25 major cancers in 2018. Eur J Cancer. 2018; 103:356-87.
Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023; 73:17-48.
Kaur J, Patil G, Geynisman DM, Ghatalia P. Role of perioperative immunotherapy in localized renal cell carcinoma. Ther Adv Med Oncol. 2023; 15:17588359231181497.
Gill DM, Hahn AW, Hale P, Maughan BL. Overview of Current and Future First-Line Systemic Therapy for Metastatic Clear Cell Renal Cell Carcinoma. Curr Treat Options Oncol. 2018; 19:6.
Tykodi SS, Pichler R. Editorial: Immune checkpoint inhibitors in renal cell carcinoma. Front Oncol. 2023; 13:1203463.
Quhal F, Mori K, Bruchbacher A, et al. First-line Immunotherapy-based Combinations for Metastatic Renal Cell Carcinoma: A Systematic Review and Network Meta-analysis. Eur Urol Oncol. 2021; 4:755-65.
Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015; 161:205-14.
Allaf M, Kim S, Harshman L, et al. Phase III RandOmized Study Comparing PErioperative Nivolumab (Nivo) versus Observation in Patients with Renal Cell Carcinoma Undergoing Nephrectomy (PROSPER, ECOG-ACRIN EA8143), a National Clinical Trials Network trial.Annal Oncol 2022; 23:S1432-33.
Tacconi EMC, Tuthill M, Protheroe A. Review of Adjuvant Therapies in Renal Cell Carcinoma: Evidence to Date. Onco Targets Ther. 2020; 13:12301-16.
Powles T, Tomczak P, Park SH, et al. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo controlled, phase 3 trial. Lancet Oncol. 2022; 23:1133-44.
Choueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. New Engl J Med. 2021; 385:683-94.
Fitzgerald KN, Motzer RJ, Lee C-H. Adjuvant therapy options in renal cell carcinoma—targeting the metastatic cascade. Nat Rev Urol. 2023; 20:179-93.
Bex A, Uzzo R, Karam J, et al. LBA66 IMmotion010: Efficacy and safety from the phase III study of atezolizumab (atezo) vs placebo (pbo) as adjuvant therapy in patients with renal cell carcinoma (RCC) at increased risk of recurrence after resection. Ann Oncol. 2022; 33:S1431-S2.
Pal SK, Uzzo R, Karam JA, et al. Adjuvant atezolizumab versus placebo for patients with renal cell carcinoma at increased risk of recurrence following resection (IMmotion010): a multicentre, randomised, double-blind, phase 3 trial. Lancet 2022; 400:1103-16.
Bex A, Russo P, Tomita Y, et al. A phase III, randomized, placebo- controlled trial of nivolumab or nivolumab plus ipilimumab in patients with localized renal cell carcinoma at high-risk of relapse after radical or partial nephrectomy (CheckMate 914). J Clin Oncol 2018; 29 (Suppl 8):VIII330.
Motzer RJ, Russo P, Grunwald V, et al. Adjuvant nivolumab plus ipilimumab versus placebo for localised renal cell carcinoma after nephrectomy (CheckMate 914): a double-blind, randomised, phase 3 trial. Lancet 2023; 401:821-32.
Motzer R, Russo P, Gruenwald V, et al. LBA4 Adjuvant nivolumab plus ipilimumab (NIVO+ IPI) vs placebo (PBO) for localized renal cell carcinoma (RCC) at high risk of relapse after nephrectomy: Results from the randomized, phase III CheckMate 914 trial. Ann Oncol. 2022; 33:S1430.
Motzer RJ, Jonasch E, Agarwal N, et al. Kidney Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2022; 20:71-90.
Ljungberg B, Albiges L, Abu-Ghanem Y, et al. European Association of Urology Guidelines on Renal Cell Carcinoma: The 2022 Update. Eur Urol. 2022; 82:399-410.
Fitzgerald KN, Lee CH. Personalizing First-Line Management of Metastatic Renal Cell Carcinoma: Leveraging Current and Novel Therapeutic Options. J Natl Compr Canc Netw 2022; 20(13).
Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. New Engl J Med 2015; 373:1803-13.
McDermott DF, Lee J-L, Bjarnason GA, et al. Open-label, singlearm phase II study of pembrolizumab monotherapy as first-line therapy in patients with advanced clear cell renal cell carcinoma. J Clin Oncol 2021; 39:1020.
Vogelzang NJ, Olsen MR, McFarlane JJ, et al. Safety and efficacy of nivolumab in patients with advanced non–clear cell renal cell carcinoma: results from the phase IIIb/IV CheckMate 374 study. Clin Genitourin Cancer. 2020; 18:461-8. e3.
Kadowaki N. [Combination of Targeted Therapy and Immunotherapy for Cancer]. Gan To Kagaku Ryoho. 2015; 42:1046-9.
Rathmell WK, Rumble RB, Van Veldhuizen PJ, et al. Management of Metastatic Clear Cell Renal Cell Carcinoma: ASCO Guideline. J Clin Oncol 2022; 40:2957-95.
Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. New Engl J Med. 2021; 384:1289-300.
Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. New Engl J Med. 2018; 378:1277-90.
Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. New Engl J Med. 2019; 380:1116-27.
Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma.New Engl J Med. 2021; 384:829-41.
Ljungberg B, Albiges L, Bedke J, et al. EAU Guidelines on Renal Cell Carcinoma. Limited March 2023 ed. Arnhem, The Netherlands.: EAU Guidelines Office; 2023; p. 29-62.
Climent C, Soriano S, Bonfill T, et al. The role of immunotherapy in non-clear cell renal cell carcinoma. Front Oncol. 2023; 13:941835.
Bergmann L, Weber S, Hartmann A, Ahrens M. Pathology and systemic therapy of non-clear cell renal cell carcinoma: an overview. Expert Rev Anticancer Ther. 2021; 21:1273-86.
Liu K, Qin Z, Xu X, et al. Comparative Risk of Renal Adverse Events in Patients Receiving Immune Checkpoint Inhibitors: A Bayesian Network Meta-Analysis. Front Oncol. 2021; 11:662731.
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. 2021; 71:209-49.
Welch HG, Albertsen PC. Prostate cancer diagnosis and treatment after the introduction of prostate-specific antigen screening: 1986-2005. J Natl Cancer Inst. 2009; 101:1325-9.
Bratt O, Drevin L, Akre O, et al. Family History and Probability of Prostate Cancer, Differentiated by Risk Category: A Nationwide Population-Based Study. J Natl Cancer Inst. 2016; 108:djw110.
Krstev S, Knutsson A. Occupational Risk Factors for Prostate Cancer: A Meta-analysis. J Cancer Prev. 2019; 24:91-111.
Campi R, Brookman-May SD, Subiela Henriquez JD, et al. Impact of Metabolic Diseases, Drugs, and Dietary Factors on Prostate Cancer Risk, Recurrence, and Survival: A Systematic Review by the European Association of Urology Section of Oncological Urology. Eur Urol Focus. 2019; 5:1029-57.
Bilusic M, Madan RA, Gulley JL. Immunotherapy of Prostate Cancer: Facts and Hopes. Clin Cancer Res. 2017; 23:6764-70.
Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. New Engl J Med. 2010; 363:411-22.
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. 2014; 15:700-12.
Markowski MC, Shenderov E, Eisenberger MA, et al. Extreme responses to immune checkpoint blockade following bipolar androgen therapy and enzalutamide in patients with metastatic castration resistant prostate cancer. Prostate. 2020; 80:407-11.
Fellner C. Ipilimumab (yervoy) prolongs survival in advanced melanoma: serious side effects and a hefty price tag may limit its use. P.T. 2012; 37:503-30.
Small EJ, Tchekmedyian NS, Rini BI, et al. A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormonerefractory prostate cancer. Clin Cancer Res 2007; 13:1810-5.
McNeel DG, Smith HA, Eickhoff JC, et al. Phase I trial of tremelimumab in combination with short-term androgen deprivation in patients with PSA-recurrent prostate cancer. Cancer Immunol Immunother. 2012; 61:1137-47.
Jochems C, Tucker JA, Tsang KY, et al. A combination trial of vaccine plus ipilimumab in metastatic castration-resistant prostate cancer patients: immune correlates. Cancer Immunol Immunother. 2014; 63:407-18.
Hegde A, Jayaprakash P, Couillault CA, et al. A Phase I Dose-Escalation Study to Evaluate the Safety and Tolerability of Evofosfamide in Combination with Ipilimumab in Advanced Solid Malignancies. Clin Cancer Res. 2021; 27:3050-60.
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. 2013; 24:1813-21.
Fizazi K, Drake CG, Beer TM, et al. Final Analysis of the Ipilimumab Versus Placebo Following Radiotherapy Phase III Trial in Postdocetaxel Metastatic Castration-resistant Prostate Cancer Identifies an Excess of Long-term Survivors. Eur Urol. 2020; 78:822-30.
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 2017; 35:40-7.
Sharma P, Pachynski RK, Narayan V, et al. Initial results from a phase II study of nivolumab (NIVO) plus ipilimumab (IPI) for the treatment of metastatic castration-resistant prostate cancer (mCRPC; CheckMate 650). J Clin Oncol. 2019; 37(7 suppl):142.
Caruso C. Anti–PD-1–CTLA4 Combo Hits Prostate Cancer. Cancer Discov. 2019; 9:569-70.
Shenderov E, Boudadi K, Fu W, et al. Nivolumab plus ipilimumab, with or without enzalutamide, in AR-V7-expressing metastatic castration-resistant prostate cancer: A phase-2 nonrandomized clinical trial. Prostate. 2021; 81:326-38.
Evan YY, Kolinsky MP, Berry WR, et al. Pembrolizumab plus docetaxel and prednisone in patients with metastatic castration-resistant prostate cancer: long-term results from the phase 1b/2 KEYNOTE-365 cohort B study. Eur Urol. 2022; 82:22-30.
Antonarakis ES, Piulats JM, Gross-Goupil M, et al. Pembrolizumab for Treatment-Refractory Metastatic Castration Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study. J Clin Oncol. 2020; 38:395-405.
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 2021; 27:3360-9.
Powles T, Yuen KC, Gillessen S,, et al. Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial. Nat Med. 2022; 28:144-53.
Fong L, Morris MJ, Sartor O, et al. A Phase Ib Study of Atezolizumab with Radium-223 Dichloride in Men with Metastatic Castration-Resistant Prostate Cancer. Clin Cancer Res. 2021; 27:4746-56.
Kwan EM, Spain L, Anton A, et al. Avelumab Combined with Stereotactic Ablative Body Radiotherapy in Metastatic Castrationresistant Prostate Cancer: The Phase 2 ICE-PAC Clinical Trial. Eur Urol. 2022; 81:253-62.
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. 2018; 6:1-12.
Cheever MA, Higano CS. PROVENGE (Sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine. Clin Cancer Res. 2011; 17:3520-6.
Wang I, Song L, Wang BY, et al. Prostate cancer immunotherapy: a review of recent advancements with novel treatment methods and efficacy. Am J Clin Exp Urol. 2022; 10:210-33.
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Bosnali, E., Akdas, E. M., Telli, E., Teke, K., & Kara, O. (2024). The role of immunotherapy in urological cancers. Archivio Italiano Di Urologia E Andrologia, 96(2). https://doi.org/10.4081/aiua.2024.12307
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