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Radiotherapy in Prostate Cancer: The Role of Pelvic Nodal Irradiation and Focal Boost to the Intraprostatic Tumor

External beam radiotherapy, along with radical prostatectomy, has been a mainstay treatment option for prostate cancer for decades and is currently recommended by numerous guidelines for the treatment of intermediate- and high-risk disease.1-3 While it is clear that radiotherapy should include the tumor, the prostate, and seminal vesicles, the role of prophylactic pelvic nodal irradiation for patients without overt evidence of regional pelvic nodal involvement has long been debated. 

Written by: Rashid Sayyid, MD MSc, & Zachary Klaassen, MD MSc
References:
  1. Eastham JA, Auffenberg GB, Barocas DA, et al. Clinically Localized Prostate Cancer: AUA/ASTRO Guideline, Part I: Introduction, Risk Assessment, Staging, and Risk-Based Management. J Urol. 2022;208(1):10-18.
  2. Schaeffer E, Srinivas S, Antonarakis ES, et al. NCCN Guidelines Insights: Prostate Cancer, Version 1.2021. J Natl Compr Canc Netw. 2021;19(2):134-143.
  3. EAU: Prostate Cancer.  https://uroweb.org/guidelines/prostate-cancer. Accessed on Oct 8, 2022.
  4. Hofman MS, Lawrentschuk N, Francis RJ, et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study. Lancet. 2020;395(10231):1208-1216.
  5. Roach M III, Marquex C, Yuo HS, et al. Predicting the risk of lymph node involvement using the pre-treatment prostate specific antigen and Gleason score in men with clinically localized prostate cancer. Int J Radiat Oncol Biol Phys. 1994;28:33-37.
  6. Roach M, Moughan J, Lawton CA, et al. Sequence of hormonal therapy and radiotherapy field size in unfavourable, localised prostate cancer (NRG/RTOG 9413): long-term results of a randomised, phase 3 trial. Lancet Oncol. 2018;19(11):1504-1515.
  7. Pommier P, Chabaud S, Lagrange J, et al. Is There a Role for Pelvic Irradiation in Localized Prostate Adenocarcinoma? Update of the Long-Term Survival Results of the GETUG-01 Randomized Study. Int J Radiat Oncol Biol Phys. 2016;96(4):759-769.
  8. Murthy V, Maitre P, Kannan S, et al. Prostate-Only Versus Whole-Pelvic Radiation Therapy in High-Risk and Very High-Risk Prostate Cancer (POP-RT): Outcomes From Phase III Randomized Controlled Trial. J Clin Oncol. 2021;39(11):1234-42.
  9. Glicksman RM, Loblaw A, Morton G, et al. Elective pelvic nodal irradiation with a simultaneous hypofractionated integrated prostate boost for localized high risk prostate cancer: Long term results from a prospective clinical trial. Radiotherap Oncol. 2021;163:21-31.
  10. Glicksman RM, Liu SK, Cheung P, et al. Elective nodal ultra hypofractionated radiation for prostate cancer: Safety and efficacy from four prospective clinical trials. Radiother Oncol. 2021;163:159-164.
  11. Wallis CJD, Huang LC, Zhao Z, et al. Association between pelvic nodal radiotherapy and patient-reported functional outcomes through 5 years among men undergoing external-beam radiotherapy for prostate cancer: An assessment of the comparative effectiveness analysis of surgery and radiation (CEASAR) cohort. Urol Oncol. 2022;40(2):56.e1-56.e8.
  12. Kerkmeijer LGW, Groen VH, Pos FJ, et al. Focal Boost to the Intraprostatic Tumor in External Beam Radiotherapy for Patients With Localized Prostate Cancer: Results From the FLAME Randomized Phase III Trial. J Clin Oncol. 2021;39(7):787-796.
  13. Wang S, Tang W, Luo H, et al. Efficacy and Toxicity of Whole Pelvic Radiotherapy Versus Prostate-Only Radiotherapy in Localized Prostate Cancer: A Systematic Review and Meta-Analysis. Front Oncol. 2022;11:796907.

Association Between Novel Anti-Androgens and Overall Survival in Non-Metastatic Castration-Resistant Prostate Cancer

Background

While there have been dramatic changes in treatment options for patients with advanced prostate cancer over the past 5 years, perhaps the greatest change has been for patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Prior to February 14, 2018, there were no agents approved by the United States Food and Drug Administration (FDA) for men with nmCRPC. Since then, three agents have been approved (apalutamide, enzalutamide, and darolutamide, in chronologic sequence of approval). While approval was initially based on improvements in metastasis-free survival, the seminal phase III trials for each of these agents have now reported overall survival data.
Written by: Zachary Klaassen, MD, MSc
References:
  1. Huggins C, Hodges CV. Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer research. 1941;1(4):293-297.

  2. Scher HI, Morris MJ, Stadler WM, et al. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016;34(12):1402-1418.

  3. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2019.

  4. Hussain M, Fizazi K, Saad F, et al. PROSPER: A phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC). Journal of Clinical Oncology. 2018;36(Suppl 6S):abstract 3.

  5. Smith MR, Saad F, Chowdhury S, et al. Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. N Engl J Med. 2018;378(15):1408-1418.

  6. Xie W, Regan MM, Buyse M, et al. Metastasis-Free Survival Is a Strong Surrogate of Overall Survival in Localized Prostate Cancer. J Clin Oncol. 2017;35(27):3097-3104.

  7. Hird AE, Magee DE, Bhindi B, et al. A Systematic Review and Network Meta-analysis of Novel Androgen Receptor Inhibitors in Non-metastatic Castration-resistant Prostate Cancer. Clin Genitourin Cancer. 2020.

  8. Small EJ, Saad F, Chowdhury S, et al. Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2019;30(11):1813-1820.

  9. Sternberg CN, Fizazi K, Saad F, et al. Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer. The New England journal of medicine. 2020;382(23):2197-2206.

  10. Smith MR, Saad F, Chowdhury S, et al. Apalutamide and Overall Survival in Prostate Cancer. European urology. 2020.

  11. Fizazi K, Shore N, Tammela TL, et al. Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide. The New England journal of medicine. 2020;383(11):1040-1049.

Beyond a VISION to Making a SPLASH: Advances in PSMA-Based Theranostics in Prostate Cancer

Background



In spite of the rapid progress and many exciting advances in the treatment of metastatic castration-resistant prostate cancer over the past few years, the disease remains incurable with a median overall survival of 12-35 months.1-4
Written by: Zachary Klaassen, MD, MSc, Medical College of Georgia, Augusta, Georgia
References:
  1. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. The New England journal of medicine. 2010;363(5):411-422.
  2. Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. The lancet oncology. 2015;16(2):152-160.
  3. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376(9747):1147-1154.
  4. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. The New England journal of medicine. 2013;369(3):213-223.
  5. Sartor O. Isotope Therapy for Castrate-Resistant Prostate Cancer: Unique Sequencing and Combinations. Cancer J. 2016;22(5):342-346.
  6. Ye X, Sun D, Lou C. Comparison of the efficacy of strontium-89 chloride in treating bone metastasis of lung, breast, and prostate cancers. J Cancer Res Ther. 2018;14(Supplement):S36-S40.
  7. James N, Pirrie S, Pope A, et al. TRAPEZE: a randomised controlled trial of the clinical effectiveness and cost-effectiveness of chemotherapy with zoledronic acid, strontium-89, or both, in men with bony metastatic castration-refractory prostate cancer. Health technology assessment. 2016;20(53):1-288.
  8. Henriksen G, Breistol K, Bruland OS, Fodstad O, Larsen RH. Significant antitumor effect from bone-seeking, alpha-particle-emitting (223)Ra demonstrated in an experimental skeletal metastases model. Cancer research. 2002;62(11):3120-3125.
  9. Bruland OS, Nilsson S, Fisher DR, Larsen RH. High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities? Clinical cancer research : an official journal of the American Association for Cancer Research. 2006;12(20 Pt 2):6250s-6257s.
  10. Sadaghiani MS, Sheikhbahaei S, Werner RA, et al. A Systematic Review and Meta-analysis of the Effectiveness and Toxicities of Lutetium-177-labeled Prostate-specific Membrane Antigen-targeted Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer. European urology. 2021;80(1):82-94.
  11. Hofman MS, Emmett L, Sandhu S, et al. [(177)Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021;397(10276):797-804.
  12. Sartor O, de Bono J, Chi KN, et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. The New England journal of medicine. 2021.

Treatment Advances in Non Metastatic Castration-Resistant Prostate Cancer

Background

Since the seminal work of Huggins and Hodges1 seventy years ago, androgen deprivation therapy (ADT) has formed the cornerstone of management for advanced prostate cancer with indications including concurrent therapy with primary curative-intent radiotherapy, salvage therapy after recurrence following local therapy, and in the treatment of metastatic disease. While efficacious, nearly all patients will eventually develop castration resistance with disease progression despite castrate levels of testosterone. Among patients who receive ADT for biochemical recurrence following radical prostatectomy or radiotherapy, the development of castration resistance typically occurs prior to the identification of metastasis on conventional imaging, nonmetastatic castration-resistant prostate cancer (nmCRPC). NmCRPC is typically identified on the basis of the PCWG3 consensus definition for prostate-specific antigen (PSA) progression on ADT, namely a 25% PSA increase from nadir (starting PSA ≥1.0 ng/mL), with a minimum rise of 2 ng/mL in the setting of castrate testosterone (< 50 ng/dL).2 In these patients, treatment is aimed at delaying the development of metastasis, preserving quality of life, and increasing overall survival.

Written by: Zachary Klaassen, MD, MSc
References:

1. Huggins, Charles, and Clarence V. Hodges. “Studies on Prostatic Cancer. I. The Effect of Castration, of Estrogen and of Androgen Injection on Serum Phosphatases in Metastatic Carcinoma of the Prostate.” Cancer Research 1, no. 4 (April 1, 1941): 293–97.
2. Scher, Howard I., Michael J. Morris, Walter M. Stadler, Celestia Higano, Ethan Basch, Karim Fizazi, Emmanuel S. Antonarakis et al. "Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the Prostate Cancer Clinical Trials Working Group 3." Journal of Clinical Oncology 34, no. 12 (2016): 1402.
3. Fizazi, Karim, Neal Shore, Teuvo L. Tammela, Albertas Ulys, Egils Vjaters, Sergey Polyakov, Mindaugas Jievaltas et al. "Darolutamide in nonmetastatic, castration-resistant prostate cancer." New England Journal of Medicine 380, no. 13 (2019): 1235-1246.
4. Hussain, Maha, Karim Fizazi, Fred Saad, Per Rathenborg, Neal D. Shore, Eren Demirhan, Katharina Modelska, De Phung, Andrew Krivoshik, and Cora N. Sternberg. "PROSPER: A phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC)." (2018): 3-3.
5. Smith, Matthew R., Fred Saad, Simon Chowdhury, Stéphane Oudard, Boris A. Hadaschik, Julie N. Graff, David Olmos et al. "Apalutamide treatment and metastasis-free survival in prostate cancer." New England Journal of Medicine 378, no. 15 (2018): 1408-1418.
6. Xie, Wanling, Meredith M. Regan, Marc Buyse, Susan Halabi, Philip W. Kantoff, Oliver Sartor, Howard Soule et al. "Metastasis-free survival is a strong surrogate of overall survival in localized prostate cancer." Journal of Clinical Oncology 35, no. 27 (2017): 3097.
7. Hird, Amanda E., Diana E. Magee, Bimal Bhindi, Y. Ye Xiang, Thenappan Chandrasekar, Hanan Goldberg, Laurence Klotz et al. "A Systematic Review and Network Meta-Analysis of Novel Androgen Receptor Inhibitors in Non-metastatic Castration-Resistant Prostate Cancer." Clinical Genitourinary Cancer (2020).
8. Tombal, Bertrand, Fred Saad, David Penson, Maha Hussain, Cora N. Sternberg, Robert Morlock, Krishnan Ramaswamy, Cristina Ivanescu, and Gerhardt Attard. "Patient-reported outcomes following enzalutamide or placebo in men with non-metastatic, castration-resistant prostate cancer (PROSPER): a multicentre, randomised, double-blind, phase 3 trial." The Lancet Oncology 20, no. 4 (2019): 556-569.
9. Saad, Fred, David Cella, Ethan Basch, Boris A. Hadaschik, Paul N. Mainwaring, Stéphane Oudard, Julie N. Graff et al. "Effect of apalutamide on health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: an analysis of the SPARTAN randomised, placebo-controlled, phase 3 trial." The Lancet Oncology 19, no. 10 (2018): 1404-1416.
10. Fizazi, Karim, Neal D. Shore, Teuvo Tammela, Iris Kuss, Marie-Aude Le Berre, Ateesha F. Mohamed, Dawn Odom, et al. “Impact of Darolutamide (DARO) on Pain and Quality of Life (QoL) in Patients (Pts) with Nonmetastatic Castrate-Resistant Prostate Cancer (NmCRPC).” Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 5000–5000.
11. Small, E. J., F. Saad, S. Chowdhury, S. Oudard, B. A. Hadaschik, J. N. Graff, D. Olmos et al. "Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer." Annals of Oncology 30, no. 11 (2019): 1813-1820.
12. Sternberg, Cora N., Karim Fizazi, Fred Saad, Neal D. Shore, Ugo De Giorgi, David F. Penson, Ubirajara Ferreira et al. "Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer." New England Journal of Medicine (2020).