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Year : 2016  |  Volume : 32  |  Issue : 4  |  Page : 255-256

Rapid bench to bed in management of metastatic prostate cancer

Department of Urology, Wake Forest University School of Medicine, Winston Salem, North Carolina, USA

Date of Web Publication28-Sep-2016

Correspondence Address:
K C Balaji
Department of Urology, Wake Forest University School of Medicine, Winston Salem, North Carolina
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0970-1591.189720

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How to cite this article:
Balaji K C. Rapid bench to bed in management of metastatic prostate cancer. Indian J Urol 2016;32:255-6

How to cite this URL:
Balaji K C. Rapid bench to bed in management of metastatic prostate cancer. Indian J Urol [serial online] 2016 [cited 2023 Apr 2];32:255-6. Available from:

Prostate cancer exemplifies heterogeneity among human cancers, is the most frequently diagnosed noncutaneous cancer in western countries and the incidence rising in countries such as India. [1],[2] Whereas most men with prostate cancer are diagnosed with apparently localized and often indolent disease, a vast majority of men dying from prostate cancer either present with metastatic disease or high risks disease such as Gleason grade >7 or non-organ confined disease. [3] Although metastatic prostate cancer (mPC) is incurable, the disease often can have a prolonged course, and thereby necessitate management strategies of a chronic disease. Men with mPC have a median survival of about 5 years. [3] Androgen deprivation therapy (ADT) has been the mainstay of treatment for men diagnosed or suspected to have mPC for decades. While ADT has proven benefit in symptomatic improvement in men with mPC, the evidence supporting improvement in survival with primary ADT alone for localized or mPC is less than convincing. Prolonged ADT is fraught with significant and severe side effects including but not limited to hot flashes, decreased energy and libido, erectile dysfunction, anemia, bone fractures, osteoporosis, increased risks of cardiac events, cognitive difficulties, and most importantly inevitable progression to castration resistance in about 3 years. [4]

The famine of options for men with mPC ended at the turn of the 21 st century and is replaced with a glut of treatment options in the management of men with advanced prostate cancer. [5] While prior chemotherapeutic agents such as mitoxantrone produced symptomatic improvement in mPC, docetaxel became the first chemotherapeutic agent to show improved survival in men with castration-resistant prostate cancer (CRPC) by two large randomized contemporaneously performed independent Phase III clinical trials. [6],[7] However, resistance to docetaxel and progression of disease eventually ensues creating a postchemotherapy space. An improvement in survival was demonstrated by another large Phase III randomized in men progressing on docetaxel chemotherapy using second-line chemotherapy with cabazitaxel belonging to the same family of taxanes but with distinct mechanisms of actions. [8] Studies are underway evaluating cabazitaxel as first-line chemotherapy in mPC. [9] Moreover, three large Phase III studies using docetaxel concurrently with ADT were done in men with androgen-sensitive mPC, of which 2 studies showed dramatic improvement in survival of over a year in men receiving docetaxel with ADT compared to ADT alone in men with large volume disease. [10]

The lack of efficacy of ADT alone in unequivocally improving survival in men mPC was not properly understood until basic research demonstrated that while serum testosterone remains low in men on ADT, sufficient levels of androgens were available in prostate cancer tissue driving disease progression. Rapid efforts to combat tissue androgens led to the development and initial approval of abiraterone, a Cyp17A inhibitor that decreases androgen synthesis, and enzalutamide, a second-generation androgen receptor antagonist in postchemotherapy space. Furthermore, abiraterone and enzalutamide also showed improvement in survival in men who have not undergone chemotherapy and therefore commonly used as first-line therapy in men progressing to castration resistance. [11],[12],[13],[14]

Sipuleucel-T was the first cancer vaccine approved for use in humans based on improvement in overall survival in men with CRPC demonstrated by 2 large Phase II and a Phase III clinical trial in patients with minimally symptomatic disease. [15] Radium-223, an alpha-emitting radioisotope was approved for treatment of men with CRPC and symptomatic bone metastasis following demonstrable improvement in overall survival in a large Phase III trial. [16] Unlike second-generation antiandrogens that were independently studied in pre- and post-chemotherapy spaces, Sipuleucel-T and Radium-223 were studied in patients with or without prior Docetaxel chemotherapy.

A total of 6 novel therapeutic agents were approved within a decade for men with metastatic CRPC, which lead to additional questions regarding the sequencing of medications. The effectiveness of docetaxel with concurrent ADT in improving overall survival in men with large volume hormone naïve mPC has resulted in the combination being used as first line therapy. Men progressing following the combination treatment or CRPC in men with low volume disease treated by ADT alone could be offered one or combination of several remaining options. A large Phase II study comparing enzalutamide to bicalutamide in with initial progression to CRPC demonstrated significant improvement in progression-free survival in men treated with enzalutamide suggesting that enzautamide may be the preferred drug in this setting. [17],[18] However, head to head comparative study between enzalutamide and abiraterone had not been done, which makes the choice between the two drugs on initial progression to CRPC somewhat empirical. The cross-resistance between second-generation antiandrogens abiraterone and enzalutamide is apparent. [19] The choice of agents is likely to depend on patient symptoms, need for prescribing steroids with abiraterone, side effect profile, costs, and availability.

While improvement in survival of over a year has been demonstrated in men with large volume hormone naïve mPC has been demonstrated with upfront docetaxel and concurrent ADT, a common theme among all studies done in men with CRPC is an improvement in overall survival ranging 2-4 months. Whether sequencing of medications will provide cumulative survival benefit remains to be answered. The heterogeneity in human cancers and prostate cancer, in particular, pose a fundamental challenge of effective targeting of all clones simultaneously with acceptable toxicities. Combinatorial, sequencing, and varying dosing strategies are being explored in use of the novel agents in mPC, which will provide additional insights for utilization of the medications. [20] While androgen signaling is well studied and successfully targeted to date, emerging data suggest a future major role for nonandrogen signaling pathways in prostate cancer that could lead to additional diagnostic and therapeutic strategies. [21]

   References Top

Jain S, Saxena S, Kumar A. Epidemiology of prostate cancer in India. Meta Gene 2014;2:596-605.  Back to cited text no. 1
Torre LA, Siegel RL, Ward EM, Jemal A. Global cancer incidence and mortality rates and trends - An update. Cancer Epidemiol Biomarkers Prev 2016;25:16-27.  Back to cited text no. 2
Patrikidou A, Loriot Y, Eymard JC, Albiges L, Massard C, Ileana E, et al. Who dies from prostate cancer? Prostate Cancer Prostatic Dis 2014;17:348-52.  Back to cited text no. 3
Quon H, Loblaw DA. Androgen deprivation therapy for prostate cancer-review of indications in 2010. Curr Oncol 2010;17 Suppl 2:S38-44.  Back to cited text no. 4
Crawford ED, Higano CS, Shore ND, Hussain M, Petrylak DP. Treating patients with metastatic castration resistant prostate cancer: A comprehensive review of available therapies. J Urol 2015;194:1537-47.  Back to cited text no. 5
Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr., Jones JA, Taplin ME, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513-20.  Back to cited text no. 6
Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502-12.  Back to cited text no. 7
de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial. Lancet 2010;376:1147-54.  Back to cited text no. 8
Shiota M, Yokomizo A, Eto M. Taxane chemotherapy for hormone-naïve prostate cancer with its expanding role as breakthrough strategy. Front Oncol 2016;5:304.  Back to cited text no. 9
Vale CL, Burdett S, Rydzewska LH, Albiges L, Clarke NW, Fisher D, et al. Addition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: A systematic review and meta-analyses of aggregate data. Lancet Oncol 2016;17:243-56.  Back to cited text no. 10
de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011;364:1995-2005.  Back to cited text no. 11
Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367:1187-97.  Back to cited text no. 12
Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013;368:138-48.  Back to cited text no. 13
Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014;371:424-33.  Back to cited text no. 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;363:411-22.  Back to cited text no. 15
Parker C, Nilsson S, Heinrich D, Helle SI, O′Sullivan JM, Fosså SD, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013;369:213-23.  Back to cited text no. 16
Penson DF, Armstrong AJ, Concepcion R, Agarwal N, Olsson C, Karsh L, et al. Enzalutamide versus bicalutamide in castration-resistant prostate cancer: The STRIVE trial. J Clin Oncol 2016. pii: JCO649285.  Back to cited text no. 17
Shore ND, Chowdhury S, Villers A, Klotz L, Siemens DR, Phung D, et al. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): A randomised, double-blind, phase 2 study. Lancet Oncol 2016;17:153-63.  Back to cited text no. 18
Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014;371:1028-38.  Back to cited text no. 19
Parente P, Parnis F, Gurney H. Challenges in the sequencing of therapies for the management of metastatic castration-resistant prostate cancer. Asia Pac J Clin Oncol 2014;10:205-15.  Back to cited text no. 20
Balaji KC. Managing Metastatic Prostate Cancer in Your Urological Oncology Practice. Switzerland: Springer International Publishing; 2016. p. 280.  Back to cited text no. 21


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