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: Christopher J.D. Wallis, MD, PhD and 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.

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 and Christopher J.D. Wallis, MD, PhD
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).

 

Darolutamide for Treatment of Castration-Resistant Prostate Cancer - Beyond the Abstract

Darolutamide is a novel anti-androgen that is recently approved for men with non-metastatic castration-resistant prostate cancer. Darolutamide is structurally different from the previously discovered androgen receptor (AR) agents enzalutamide, bicalutamide and apalutamide. Early phase trials showed promising results with overall safety profiles that are generally well-tolerated. However, the trial that ultimately led to the approval of darolutamide was the ARAMIS trial which was a Phase III randomized, double-blind, placebo-controlled trial that evaluated the safety and efficacy of darolutamide in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) who are at high risk for developing metastasis.1
Written by: Jeanny B. Aragon-Ching, M.D., F.A.C.P.
References:
  1. 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.
  2. Hussain, Maha, Karim Fizazi, Fred Saad, Per Rathenborg, Neal Shore, Ubirajara Ferreira, Petro Ivashchenko et al. "Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer." New England Journal of Medicine 378, no. 26 (2018): 2465-2474.
  3. Smith, M. R., M. K. Yu, and E. J. Small. "Apalutamide and Metastasis-free Survival in Prostate Cancer." The New England journal of medicine 378, no. 26 (2018): 2542-2542.