June 2014, Vol 3, No 4
Androgen Suppression in Castration-Resistant Prostate Cancer
Prostate cancer is the most frequently diagnosed cancer in men other than skin cancer and is the second-leading cause of cancer death in men in the United States.1,2 An estimated 238,590 new cases of prostate cancer will have occurred in the United States during 2013, with an estimated 29,720 deaths.1,2 Most patients have low-risk, clinically localized disease at diagnosis and can be treated effectively (or even cured) with prostatectomy (open, laparoscopic, or robotic- assisted) and radiation therapy (external beam radiation or brachytherapy).1 However, 10% to 20% of patients are diagnosed with locally advanced or metastatic disease, and an additional 10% to 20% of patients diagnosed with localized disease will eventually develop metastases despite surgery and radiation.3,4
When prostate cancer progresses – marked by elevated levels of prostate-specific antigen (PSA), new metastases, and progression of existing metastases – despite confirmation of castrate levels of testosterone, it is referred to as castration-resistant prostate cancer (CRPC).5,6 A review characterizing the CRPC population revealed that 10% to 20% of patients develop CRPC within 5 years of follow-up.7 Prostate cancer deaths are typically the result of metastatic CRPC (mCRPC), and historically the median survival for men with mCRPC has been less than 2 years.8 The exact mechanism of transition from castration-sensitive prostate cancer to castration- resistant disease is not fully elucidated, but it is now understood that despite castrate levels of androgens, the androgen receptor (AR) remains active and continues to drive prostate cancer progression.9-13 In fact, in mCRPC, the AR remains hypersensitive to even low levels of androgen, increasing the stimulatory effects of testosterone and dihydrotestosterone (DHT).14-16 In addition, it has been shown that, in mCRPC, the tumor itself is an additional source of androgen.9,17
Androgen Deprivation Therapy
Since the 1940s, when Huggins and colleagues demonstrated the responsiveness of prostate cancer to androgen deprivation, ie, that lowering serum testosterone levels by surgical castration or injection of estrogens induces a major regression of advanced prostate cancer and provides rapid relief from symptoms in patients with metastatic disease,18,19 the mainstay of treatment for advanced and metastatic prostate cancer has been androgen deprivation therapy (ADT; also known as androgen suppression therapy or hormonal therapy). In ADT, castration is accomplished either surgically by bilateral orchiectomy (surgical castration), or pharmacologically by the use of gonadotropin-releasing hormone (GnRH; also known as luteinizing hormone–releasing hormone [LHRH]) agonists, GnRH (or LHRH) antagonists, or antiandrogens – or their combination, which is referred to as combination (or maximal) androgen blockade (Table 1).2,3,20-25
Removal of the testicular source of androgens leads to a considerable decline in testosterone levels and induces a hypogonadal status, although a very low level of testosterone (known as the “castration level”) persists.25 Surgical castration is still considered the “gold standard” for ADT, against which all other treatments are rated, especially in Europe.25 In the United States, practice patterns favor GnRH agonists over orchiectomy because of their reversibility, ease of administration, and acceptability to patients.26 Results from a large retrospective study showed that external beam radiation therapy with ADT confers survival equal to that of radical prostatectomy in men with high-risk prostate cancer.27
ADT consistently results in a 90% to 95% reduction in circulating levels of testosterone.4 Synthesis of androgens outside the testes contributes to disease progression in CRPC. ADTs decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumor; therefore, although the majority of patients with metastatic disease initially respond to hormonal therapy, almost all of them will eventually progress after an average of 14 to 24 months, despite maintenance of castrate serum testosterone levels <50 ng/mL.2,28-31
New Hormonal Therapy Agents
Two new hormonal therapy agents targeting the AR pathway have recently been approved by the FDA for the treatment of patients with mCRPC: abiraterone acetate and enzalutamide (MDV3100) (Table 2).32,33
The FDA approval of abiraterone acetate was based on the results of 2 randomized, placebo-controlled, multicenter phase 3 studies (Study 1 and Study 2) in patients who had mCRPC who were using a GnRH agonist or had been previously treated with orchiectomy. Patients with prior ketoconazole treatment for prostate cancer and a history of adrenal gland or pituitary disorders were excluded from these trials.32 Study 1 enrolled 1195 patients with mCRPC who had received prior docetaxel chemotherapy. Results from a survival analysis conducted when 775 deaths (97% of the planned number of deaths for final analysis) were observed showed that overall survival was longer for patients treated with abiraterone acetate than for those who received placebo (Figure 1).32 Study 2 enrolled 1088 patients with mCRPC who had not received prior cytotoxic chemotherapy. At the protocol-prespecified third interim analysis for overall survival, 37% of patients (200 of 546) treated with abiraterone acetate, compared with 43% of patients (234 of 542) treated with placebo, had died. As in Study 1, overall survival was longer with abiraterone acetate than with placebo (Figure 1).32
In both studies, abiraterone acetate was administered at a dose of 1000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. The most common adverse drug reactions (?10%) reported in the 2 randomized studies that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flushes, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion. The most common laboratory abnormalities (>20%) reported in the 2 randomized clinical trials that occurred more commonly (?2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia.32
Coadministration of low-dose prednisone is necessary with abiraterone acetate to ameliorate hypertension, hypokalemia, and fluid overload resulting from mineralocorticoid excess induced by CYP17 inhibition.34 While coadministration of prednisone is manageable in patients with mCRPC, longer-term use in earlier disease phases could be problematic due to potential side effects (eg, diabetes, weight gain, Cushing syndrome, and osteoporosis).
The FDA approval of enzalutamide was based on the results of a randomized, placebo-controlled, multicenter phase 3 study (AFFIRM) in 1199 patients with mCRPC who had received prior docetaxel-based therapy.33,35 The primary end point was overall survival. The prespecified interim analysis showed a statistically significant improvement in overall survival in patients in the enzalutamide group compared with those receiving placebo (Figure 2).33,35
The most common adverse drug reactions (?5%) with enzalutamide were asthenia/fatigue, back pain, diarrhea, arthralgia, hot flushes, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade ?3 adverse reactions were reported among 47% of enzalutamide-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of enzalutamide-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% (n=7) of the enzalutamide-treated patients compared with 0% of the placebo-treated patients.33
Enzalutamide has also been investigated in prechemotherapy CRPC patients, including both metastatic and nonmetastatic disease in the PREVAIL trial, a randomized, double-blind, placebo-controlled phasetrial that included 1715 patients who had progressed following treatment with an LHRH analog only, as well as patients who had progressed following treatment with both an LHRH analog and an antiandrogen. The primary end points were radiographic progression-free and overall survival. Due to positive results in both end points (30% reduction in the risk of death, hazard ratio [HR] 0.70, P<.0001; 81% reduction in the risk of radiographic progression or death, HR 0.19, P<0001), the Independent Data Monitoring Committee recommended the study be stopped and patients treated with placebo be offered enzalutamide.36
Investigational ADT Agents for CRPC
More recently, other drugs that act along the androgen signaling pathway, such as orteronel (TAK-700),37 galeterone (TOK-001),38,39 and ARN-509,40 have shown promise in clinical trials (Table 3).
Complications Associated With Androgen Suppression
Because a diagnosis of prostate cancer does not alter the life expectancy for most men (ie, most men diagnosed with prostate cancer will die of something other than their cancer), the benefits of ADT must be weighed against ADT-related adverse effects that are a consequence of the induced sex steroid deficiency.26,41 ADT has been shown to cause weight gain, decreased lean muscle mass, and increased fat mass leading to insulin resistance and diabetes; increased cholesterol and triglycerides leading to cardiovascular disease; and loss of bone mineral density causing osteoporosis and increased fracture risk.26,41 Men commencing ADT should be counseled about and be carefully monitored for these and other ADT-induced complications, which include vasomotor flushing (hot flashes), sexual dysfunction (loss of libido, impotence), fatigue, and anemia (Table 4).26,42-47
For more than 70 years, the benefits of androgen deprivation in the management of CRPC have been recognized. Two new hormonal therapy agents (abiraterone acetate and enzalutamide) have recently been granted FDA approval for the treatment of patients with CRPC, and additional hormonal therapy agents are under investigation in clinical trials.
However, although the majority of patients with mCRPC initially respond to hormonal therapy, almost all of them will eventually progress. In addition, ADT is associated with a number of side effects, including vasomotor flushing, sexual dysfunction, fatigue, anemia, and metabolic complications, as well as effects on cardiovascular health and bone density. Therefore, clinicians should consider comorbidities and functional status of patients before initiating ADT, and the risk-benefit ratio related to ADT must be assessed for each individual patient – keeping in mind that the best way of preventing side effects is to use ADT only when it is absolutely indicated.46
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8. Cookson MS, Roth BJ, Dahm P, et al. Castration-resistant prostate cancer: AUA Guideline. J Urol. 2013;190:429-438. www.auanet.org/common/pdf/education/clini cal-guidance/Castration-Resistant-Prostate-Cancer.pdf. Accessed August 31, 2013.
9. 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;68:4447-4454.
10. Mohler JL, Titus MA, Bai S, et al. Activation of the androgen receptor by intratumoral bioconversion of androstanediol to dihydrotestosterone in prostate cancer. Cancer Res. 2011;71:1486-1496.
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13. Yuan X, Balk SP. Mechanisms mediating androgen receptor reactivation after castration. Urol Oncol. 2009;27:36-41.
14. Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10:33-39.
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16. Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68:6407-6415.
17. Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006;66:2815-2825.
18. 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 Res. 1941;1:293-297.
19. Huggins C, Stevens RE Jr, Hodges CV. Studies on prostatic cancer, II: the effects of castration on advanced carcinoma of the prostate gland. Arch Surg. 1941;43:209-223.
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21. National Cancer Institute. Prostate Cancer Treatment (PDQ). Bethesda, MD: National Cancer Institute; 2013. www.cancer.gov/cancertopics/pdq/treatment/prostate/HealthProfessional. Updated November 19, 2013. Accessed September 1, 2013.
22. Wirth MP, Hakenberg OW, Froehner M. Antiandrogens in the treatment of prostate cancer. Eur Urol. 2007;51:306-313.
23. Sridhar SS, Freedland SJ, Gleave ME, et al. Castration-resistant prostate cancer: from new pathophysiology to new treatment. Eur Urol. 2014;65:289-299.
24. American Cancer Society. Hormone (androgen deprivation) therapy for prostate cancer. www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-treating-hormone-therapy. Updated March 2013. Accessed September 1, 2013.
25. Heidenreich A, Bastian PJ, Bellmunt J, et al. Guidelines on Prostate Cancer. Arnheim, The Netherlands: European Association of Urology; 2013. www.uroweb.org/gls/pdf/09_Prostate_Cancer_LR.pdf. Updated March 2013. Accessed September 3, 2013.
26. Saylor PJ, Smith MR. Adverse effects of androgen deprivation therapy: defining the problem and promoting health among men with prostate cancer. J Natl Compr Canc Netw. 2010;8:211-223.
27. Boorjian SA, Karnes RJ, Viterbo R, et al. Long-term survival after radical prostatectomy versus external-beam radiotherapy for patients with high-risk prostate cancer. Cancer. 2011;117:2883-2891.
28. Lam JS, Leppert JT, Vemulapalli SN, et al. Secondary hormonal therapy for advanced prostate cancer. J Urol. 2006;175:27-34.
29. Eisenberger MA, Blumenstein BA, Crawford ED, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med. 1998;339:1036-1042.
30. Crawford ED, Eisenberger MA, McLeod DG, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989;321:419-424.
31. Fitzpatrick JM, Anderson J, Sternberg CN, et al. Optimizing treatment for men with advanced prostate cancer: expert recommendations and the multidisciplinary approach. Crit Rev Oncol Hematol. 2008;68(suppl 1):S9-S22.
32. Zytiga [package insert]. Horsham, PA: Janssen Biotech, Inc; 2013.
33. Xtandi [package insert]. Northbrook, IL: Astellas Pharma US, Inc; 2012.
34. de Bono JS, Logothetis CJ, Molina A, et al; COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005.
35. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197.
36. Medivation and Astellas announce the phase 3 PREVAIL trial of enzalutamide meets both co-primary endpoints of overall survival and radiographic progression-free survival in chemotherapy-naive patients with advanced prostate cancer [press release]. San Francisco, CA, and Tokyo, Japan: Marketwired; October 22, 2013. http://investors.medivation.com/releasedetail.cfm?ReleaseID=798880. Accessed January 3, 2014.
37. Takeda announces unblinding of phase 3 study of orteronel in patients with metastatic, castration-resistant prostate cancer that progressed post-chemotherapy based on interim analysis [press release]. Osaka, Japan, and Cambridge, MA: Takeda Pharmaceutical Co Ltd; July 26, 2013. www.takeda.com/news/2013/20130726_5894.html. Accessed September 11, 2013.
38. Tokai Pharmaceuticals. About galeterone (TOK-001): three distinct mechanisms of action. www.tokaipharma.com/programs-tok-001.php. Accessed September 12, 2013.
39. Tokai Pharmaceuticals. About galeterone: ARMOR. http://tokaipharma.com/programs-armor.php. Accessed October 18, 2013.
40. 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. 2013;31:3525-3530.
41. Grossmann M, Zajac JD. Androgen deprivation therapy in men with prostate cancer: how should the side effects be monitored and treated? Clin Endocrinol (Oxf). 2011;74:289-293.
42. Martín-Merino E, Johansson S, Morris T, et al. Androgen deprivation therapy and the risk of coronary heart disease and heart failure in patients with prostate cancer: a nested case-control study in UK primary care. Drug Saf. 2011;34:1061-1077.
43. Azoulay L, Yin H, Benayoun S, et al. Androgen-deprivation therapy and the risk of stroke in patients with prostate cancer. Eur Urol. 2011;60:1244-1250.
44. Taylor LG, Canfield SE, Du XL. Review of major adverse effects of androgen-deprivation therapy in men with prostate cancer. Cancer. 2009;115:2388-2399.
45. Kintzel PE, Chase SL, Schultz LM, et al. Increased risk of metabolic syndrome, diabetes mellitus, and cardiovascular disease in men receiving androgen deprivation therapy for prostate cancer. Pharmacotherapy. 2008;28:1511-1522.
46. Ahmadi H, Daneshmand S. Androgen deprivation therapy: evidence-based management of side effects. BJU Int. 2013;111:543-548.
47. Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. 2012;379:39-46.
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