Advances in systemic therapies for metastatic castration-resistant prostate cancer - Beyond the Abstract

Systemic treatment for metastatic castration-resistant prostate cancer (mCRPC) is rapidly evolving with several drugs approved in recent years. The utility of immunotherapy, chemotherapy, novel anti-androgen and androgen-targeted signaling agents for this particular patient population has been well-established [1]. This article discusses the pivotal trials that led to the approval of these drugs as well as a proposed algorithm in the care of patients with mCRPC.

In addition to denosumab for suitable men with bone involvement [2], androgen deprivation therapy (ADT) in the form of degarelix has been utilized, which is non-inferior to leuprolide in all comers with metastatic prostate cancer [3]. Following inevitable rise in PSA, chemotherapy with docetaxel [4] followed by cabazitaxel [5] is largely reserved for fit, symptomatic patients, while anti-androgen agents including abiraterone acetate with prednisone [6], enzalutamide [7], and radium-223 [8] should all be considered well-tolerated and effective treatments. Management prolonging survival also includes the autologous dendritic cell vaccine, sipuleucel-T [9] although no significant prostate specific antigen (PSA) responses have been seen. Novel prospects on the horizon for this ultimately fatal condition also include an androgen receptor antagonist, ARN-509 [10], and the dual MET and VEGF receptor inhibitor, cabozantinib [11] and [12], although the latter has shown preliminary negative updated results.

1. El-Amm J, Aragon-Ching JB. The changing landscape in the treatment of metastatic castration resistant prostate cancer. Ther Adv Med Oncol. 2013;5(1): 25-40
2. Fizazi K, Carducci M, Smith M et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomized, double-blind study. Lancet 377 (9768), 813-822 (2011).
3. Crawford ED, Tombal B, Miller K et al. A Phase III extension trial with a 1-arm crossover from leuprolide to degarelix: comparison of gonadotropin-releasing hormone agonist and antagonist effect on prostate cancer. J. Urol. 186(3), 889-897 (2011).
4. Tannock IF, De Wit R, Berry WR et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N. Engl. J. Med. 351(15), 1502-1512 (2004).
5. 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.
6. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138–148
7. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in Metastatic Prostate Cancer before Chemotherapy. N Engl J Med. 2014 Jul 31;371(5):424-33
8. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013 Jul 18;369(3):213-23
9. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer. N Engl J Med. 2010 Jul 29;363(5):411-22
10. Rathkopf DE, Morris MJ, Fox JJ et al. Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer. J Clin. Oncol. 31(28), 3525-3530 (2013).
11. Study of Cabozantinib (XL184) Versus Prednisone in Men With Metastatic Castration-resistnat Prostate Cancer Previously Treated With Docetaxel and Abiraterone or MDV3100 (COMET-1).
12. Study of Cabozantinib (XL184) Versus Mitoxantrone Plus Prednisone in Men With Previously Treated Symptomatic Castration-resistant Prostate Cancer (COMET-2).

Written by:
Manish Pant, M.D. and Jeanny B. Aragon-Ching, M.D., F.A.C.P.
Division of Hematology/Oncology, Department of Medicine, George Washington University Medical Center

Abstract: Advances in systemic therapies for metastatic castration-resistant prostate cancer


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