Castration-resistant prostate cancer: Treatments targeting the androgen pathway
- Nancy A Dawson, MD
Nancy A Dawson, MD
- Professor of Medicine
- Lombardi Comprehensive Cancer Center
- Georgetown University
- Charles J Ryan, MD
Charles J Ryan, MD
- Professor of Clinical Medicine and Urology
- UCSF/Helen Diller Family Comprehensive Cancer
- Section Editors
- Nicholas Vogelzang, MD
Nicholas Vogelzang, MD
- Section Editor — Prostate Cancer
- Professor of Medicine
- University of Nevada School of Medicine
- US Oncology Research
- Jerome P Richie, MD, FACS
Jerome P Richie, MD, FACS
- Section Editor — Cancer of the Urethra, Penis, and Ureter; Urologic Surgery; Prostate Cancer
- Elliott Carr Cutler Professor of Surgery
- Harvard Medical School
- W Robert Lee, MD, MS, MEd
W Robert Lee, MD, MS, MEd
- Section Editor — Prostate Cancer
- Professor of Radiation Oncology
- Duke University Medical Center
Androgen deprivation therapy (ADT), either alone or in combination with chemotherapy, is generally the initial treatment for men with metastatic prostate cancer. Standard approaches to ADT include bilateral orchiectomy or medical orchiectomy using a gonadotropin releasing hormone (GnRH) agonist, which may be given alone or in combination with an antiandrogen (combined androgen blockade). (See "Initial systemic therapy for castration-sensitive prostate cancer".)
Despite initial response rates of 80 to 90 percent, nearly all men eventually develop progressive disease following ADT; this is referred to as castration-resistant prostate cancer. Contemporary research in men with castration-resistant prostate cancer has led to the development of multiple agents that improved overall survival in phase III trials (table 1).
Insights into the mechanisms by which androgens stimulate growth of prostate cancer cells is leading to the development of new treatments with clinically significant activity in men with castration-resistant prostate cancer. These approaches are discussed here.
Overviews of the management of advanced castration-sensitive and castration-resistant prostate cancer are presented separately. (See "Overview of the treatment of disseminated castration-sensitive prostate cancer" and "Overview of the treatment of castration-resistant prostate cancer (CRPC)".)
Rationale — Contemporary research has demonstrated that androgen-based pathways have a clinically significant role in the progression of castration-resistant prostate cancer. In addition to androgen production by the adrenal gland and testis, several of the enzymes involved in the synthesis of testosterone and dihydrotestosterone, including cytochrome P450 17-alpha-hydroxysteroid dehydrogenase (CYP17), are highly expressed in tumor tissue .
- Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res 2008; 68:4447.
- Barrie SE, Potter GA, Goddard PM, et al. Pharmacology of novel steroidal inhibitors of cytochrome P450(17) alpha (17 alpha-hydroxylase/C17-20 lyase). J Steroid Biochem Mol Biol 1994; 50:267.
- Attard G, Reid AH, A'Hern R, et al. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol 2009; 27:3742.
- Potter GA, Barrie SE, Jarman M, Rowlands MG. Novel steroidal inhibitors of human cytochrome P45017 alpha (17 alpha-hydroxylase-C17,20-lyase): potential agents for the treatment of prostatic cancer. J Med Chem 1995; 38:2463.
- Visakorpi T, Hyytinen E, Koivisto P, et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet 1995; 9:401.
- Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004; 10:33.
- Edwards J, Krishna NS, Grigor KM, Bartlett JM. Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer. Br J Cancer 2003; 89:552.
- Gregory CW, Johnson RT Jr, Mohler JL, et al. Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res 2001; 61:2892.
- Watson PA, Chen YF, Balbas MD, et al. Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor. Proc Natl Acad Sci U S A 2010; 107:16759.
- Guo Z, Yang X, Sun F, et al. A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res 2009; 69:2305.
- Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014; 371:1028.
- Antonarakis ES, Lu C, Luber B, et al. Clinical Significance of Androgen Receptor Splice Variant-7 mRNA Detection in Circulating Tumor Cells of Men With Metastatic Castration-Resistant Prostate Cancer Treated With First- and Second-Line Abiraterone and Enzalutamide. J Clin Oncol 2017; :JCO2016701961.
- Antonarakis ES, Lu C, Luber B, et al. Androgen Receptor Splice Variant 7 and Efficacy of Taxane Chemotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer. JAMA Oncol 2015; 1:582.
- de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364:1995.
- Fizazi K, Scher HI, Molina A, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2012; 13:983.
- Logothetis CJ, Basch E, Molina A, et al. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol 2012; 13:1210.
- Rathkopf DE, Smith MR, de Bono JS, et al. Updated interim efficacy analysis and long-term safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients without prior chemotherapy (COU-AA-302). Eur Urol 2014; 66:815.
- 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. Lancet Oncol 2015; 16:152.
- Goodman OB, et al. Exploratory analysis of the visceral disease (VD) patient subset in COU-AA-301, a phase III study of abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 2013; 31: (suppl 6; abstr 14).
- Ryan CJ, Shah S, Efstathiou E, et al. Phase II study of abiraterone acetate in chemotherapy-naive metastatic castration-resistant prostate cancer displaying bone flare discordant with serologic response. Clin Cancer Res 2011; 17:4854.
- Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013; 368:138.
- Basch E, Autio K, Ryan CJ, et al. Abiraterone acetate plus prednisone versus prednisone alone in chemotherapy-naive men with metastatic castration-resistant prostate cancer: patient-reported outcome results of a randomised phase 3 trial. Lancet Oncol 2013; 14:1193.
- Attard G, Borre M, Gurney H, et al. A phase IV, randomized, double-blind, placebo-controlled study of continued enzalutamide post prostate-specific antigen progression in men with chemotherapy-naïve metastatic castration-resistant prostate cancer (abstract 5004). 2017 American Society of Clinical Oncology meeting.
- Smith MR, Saad F, Rathkopf DE, et al. Clinical Outcomes from Androgen Signaling-directed Therapy after Treatment with Abiraterone Acetate and Prednisone in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302. Eur Urol 2017; 72:10.
- Fizazi K, Chi KN, de Bono JS, et al. Low incidence of corticosteroid-associated adverse events on long-term exposure to low-dose prednisone given with abiraterone acetate to patients with metastatic castration-resistant prostate cancer. Eur Urol 2016.
- Scher HI, Beer TM, Higano CS, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet 2010; 375:1437.
- Rathkopf D, Liu G, Carducci MA, et al. Phase I dose-escalation study of the novel antiandrogen BMS-641988 in patients with castration-resistant prostate cancer. Clin Cancer Res 2011; 17:880.
- Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367:1187.
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203415lbl.pdf?et_cid=29930410&et_rid=463634184&linkid=http%3a%2f%2fwww.accessdata.fda.gov%2fdrugsatfda_docs%2flabel%2f2012%2f203415lbl.pdf (Accessed on September 04, 2012).
- Fizazi K, Scher HI, Miller K, et al. Effect of enzalutamide on time to first skeletal-related event, pain, and quality of life in men with castration-resistant prostate cancer: results from the randomised, phase 3 AFFIRM trial. Lancet Oncol 2014; 15:1147.
- Miller K, et al. Effect of enzalutamide on health-related quality of life (HRQoL) in men with metastatic castration-resistant prostate cancer (mCRPC) following docetaxel-based therapy: Results from the AFFIRM study. J Clin Oncol 2013; 31: (suppl 6; abstr 17).
- Sternberg C, et al. Outcomes in elderly patients with metastatic castration-resistant prostate cancer (mCRPC) treated with the androgen receptor inhibitor enzalutamide: Results from the phase III AFFIRM trial. J Clin Oncol 2013; 31: (suppl 6; abstr 16).
- Scher H, et al. Impact of on-study corticosteroid use on efficacy and safety in the phase III AFFIRM study of enzalutamide (ENZA), an androgen receptor inhibitor. J Clin Oncol 2013; 31: (suppl 6; abstr 6).
- Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371:424.
- Loriot Y, Miller K, Sternberg CN, et al. Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer (PREVAIL): results from a randomised, phase 3 trial. Lancet Oncol 2015; 16:509.
- Evans CP, Higano CS, Keane T, et al.. the PREVAIL study: primary outcomes by site and extent of baseline disease for enzalutamide-treated men with chemotherapy-naïve metastatic castration-resistant prostate cancer. Eur Urol 2016.
- Beer TM, Armstrong AJ, Rathkopf D, et al. Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study. Eur Urol 2017; 71:151.
- Shore ND, Chowdhury S, Villers A, 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.
- Penson DF, Armstrong AJ, Concepcion R, et al. Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial. J Clin Oncol 2016; 34:2098.
- Azad AA, Eigl BJ, Murray RN, et al. Efficacy of enzalutamide following abiraterone acetate in chemotherapy-naive metastatic castration-resistant prostate cancer patients. Eur Urol 2015; 67:23.
- de Bono JS, Chowdhury S, Feyerabend S, et al. Antitumour Activity and Safety of Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer Previously Treated with Abiraterone Acetate Plus Prednisone for ≥24 weeks in Europe. Eur Urol 2017.
- Chi KN, Annala M, Sunderland K, et al. A randomized phase II cross-over study of abiraterone + prednisone versus enzalutamide for patients with metastatic, castration-resistant prostate cancer (abstract 5002). 2017 American Society of Clinical Oncology meeting.
- Efstathiou E, Titus MA, Wen S, et al. Enzalutamide (ENZA) in combination with abiraterone acetate (AA) in bone metastatic castration resistant prostate cancer (mCRPC) (abstract 5000). 2014 American Society of Clinical Oncology meeting.
- Loriot Y, Bianchini D, Ileana E, et al. Antitumour activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100). Ann Oncol 2013; 24:1807.
- Noonan KL, North S, Bitting RL, et al. Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann Oncol 2013; 24:1802.
- Bianchini D, Lorente D, Rodriguez-Vida A, et al. Antitumour activity of enzalutamide (MDV3100) in patients with metastatic castration-resistant prostate cancer (CRPC) pre-treated with docetaxel and abiraterone. Eur J Cancer 2014; 50:78.
- MOLECULAR PATHWAYS
- - Androgen synthesis inhibitors
- - Androgen receptor antagonists
- - Prior docetaxel chemotherapy
- - Chemotherapy-naïve patients
- - Prior enzalutamide therapy
- - Retreatment with abiraterone
- Clinical role
- ANDROGEN RECEPTOR ANTAGONISTS
- - Prior docetaxel chemotherapy
- - Chemotherapy-naïve patients
- - Prior abiraterone therapy
- Other androgen receptor antagonists
- ABIRATERONE VERSUS ENZALUTAMIDE
- COMBINING ABIRATERONE AND ENZALUTAMIDE
- SURVEILLANCE DURING TREATMENT
- SUMMARY AND RECOMMENDATIONS