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T h e new england journal o f medicine

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Enzalutamide — A Major Advance in the Treatment of Metastatic Cancer Nicholas J. Vogelzang, M.D.

In this issue of the Journal, Scher et al. describe it was overexpressed as the cancer progressed; it the strikingly positive results of a phase 3 trial of could mutate, allowing stimulation by a variety a new agent, enzaluta- of weak ; and it could be activated by mide, as compared with in metastatic autocrine production of androgens from tumor -resistant .1 Not only was cells obtained from patients with the disease. survival significantly improved among patients Chen et al. then conducted an elegant series of who had undergone previous chemotherapy with experiments that involved the synthesis of bicalu- docetaxel (a treatment that is a watershed event tamide analogues with improved inhibitory ca- in the lives of most patients), but the incidence pacity5 and ultimately led to the discovery of of adverse events of grade 3 or higher was lower . When phase 1 and phase 2 trials among the patients receiving enzalutamide than confirmed the safety and activity of enzaluta- among those receiving placebo (a finding that mide,6 the phase 3 trial was launched; the trial suggests that the “” of placebo is related design was virtually identical to that used to ob- to underlying disease-related symptoms). How tain Food and Drug Administration (FDA) ap- did the field get to this point, and what are the proval of abiraterone.7 next steps forward? Although abiraterone inhibits syn- The first nonsteroidal antiandrogen agents — thesis and lowers levels to nearly , nilutamide, and bicalutamide2 — were undetectable levels, it does not affect androgen- shown to be less effective than castration in receptor signaling, which may remain active and cases of metastatic castration-resistant prostate thereby cause disease progression (perhaps by cancer, but is still widely used as a means of alternative androgenic ). En­ moderately effective secondary therapy zalutamide does not lower androgen levels but because of an excellent safety profile.3 Dozens instead inhibits androgen-receptor signaling by of randomized phase 3 trials then compared competitively inhibiting the binding of andro- testosterone ablation plus an antiandrogen (termed gens without stimulation of the androgen recep- combined androgen blockade) with testosterone tor. Tumor- growth then requires androgen ablation alone. Meta-analyses concluded that the binding to the , followed by addition of flutamide or nilutamide prolonged nuclear translocation and DNA binding; enzalu- survival by 2 to 5% at 5 years. One study of tes- tamide inhibits both steps, even in patients with tosterone ablation alone as compared with testos- androgen-receptor overexpression and resistance terone ablation with bicalutamide showed a sur- to other . These potentially non- vival advantage for the combination.4 Therefore, overlapping and synergistic actions of abiraterone since the mid-1990s, bicalutamide has been the and enzalutamide have led to the proposal for standard of care for patients receiving combined a phase 3 trial comparing enzalutamide with androgen blockade. enzalutamide plus abiraterone (comparisons with Subsequently, the androgen receptor was abiraterone alone would also be interesting) shown to be central to the biologic features of (Morris M, Memorial Sloan-Kettering Cancer metastatic castration-resistant prostate cancer: Center: personal communication).

1256 n engl j med 367;13 nejm.org september 27, 2012 editorials

What are the limitations to the use of enzalu- with metastatic castration-resistant prostate can- tamide (which has just received FDA approval on cer. The relative effectiveness of enzalutamide in the basis of the study by Scher et al.)? First, patients who have previously received abiraterone enzalutamide is likely to be active in all patients is unknown, although as noted above, the two with metastatic castration-resistant prostate agents are theoretically not cross-resistant. cancer in whom the androgen receptor is still In conclusion, enzalutamide, a new, highly driving the disease, regardless of whether the effective, and safe nonsteroidal antiandrogen, patients have received treatment with docetaxel. extends survival and will become widely used in A phase 3 trial involving patients who have not patients with metastatic castration-resistant pros- been treated with docetaxel is complete and tate cancer. It will be used sequentially with oth- should be reported shortly (ClinicalTrials.gov er active agents, such as docetaxel, abiraterone, number, NCT01212991). cabazitaxel, radium-223, and immunotherapy. It Second, assessment of androgen-receptor ac- will be studied much earlier in the disease course. tivity in patients with metastatic castration-resis- In addition, it is likely to supplant bicalutamide in tant prostate cancer is not clinically available, so combined androgen blockade after appropriate all patients deserve a therapeutic trial of enzalu- phase 3 trials have been completed. tamide. However, Tzelepi et al.8 recently reported Disclosure forms provided by the author are available with the that approximately 25% of analyzed tumors ob- full text of this article at NEJM.org. tained from patients with metastatic castration- From the Comprehensive Cancer Centers of Nevada, Las Vegas. resistant prostate cancer have no androgen recep- tors yet show marked up-regulation of the gene 1. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med for the ubiquitin-conjugating E2C and 2012;367:1187-97. other mitotic genes that are independent of regu- 2. Furr BJ, Valcaccia B, Curry B, Woodburn JR, Chesterson G, lation by androgen receptors. The extrapolation Tucker H. ICI 176,334: a novel non-steroidal, peripherally selec- tive antiandrogen. J Endocrinol 1987;113:R7-R9. of these data indicates that such patients will 3. Small EJ, Vogelzang NJ. Second-line hormonal therapy for have no response or only a minimal response to advanced prostate cancer: a shifting paradigm. J Clin Oncol enzalutamide. Characterization of the spectrum 1997;15:382-8. 4. Akaza H, Hinotsu S, Usami M, et al. Combined androgen of enzalutamide activity as a function of the blockade with bicalutamide for advanced prostate cancer: long- heterogeneity of the androgen-signaling pathway term follow-up of a phase 3, double-blind, randomized study for should be a priority of future translational trials. survival. Cancer 2009;115:3437-45. 5. Chen CD, Welsbie DS, Tran C, et al. Molecular determinants Third, enzalutamide crosses the blood–brain of resistance to antiandrogen therapy. Nat Med 2004;10:33-9. barrier and apparently leads to sensitization to 6. Scher HI, Beer TM, Higano CS, et al. Antitumour activity of seizures in small numbers of patients.1 The abil- MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet 2010;375:1437-46. ity to cross the blood–brain barrier may be a 7. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and therapeutic advantage in patients with advanced increased survival in metastatic prostate cancer. N Engl J Med epidural or meningeal disease but calls for cau- 2011;364:1995-2005. 8. Tzelepi V, Zhang J, Lu JF, et al. Modeling a lethal prostate tion. Another new nonsteroidal antiandrogen, cancer variant with small-cell carcinoma features. Clin Cancer ARN-509, seems to have a similar potency but Res 2012;18:666-77. less penetrance of the central .9 9. Clegg NJ, Wongvipat J, Joseph JD, et al. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res 2012;72: Fourth, this enrolled very few 1494-503. patients who had previously received abiraterone, DOI: 10.1056/NEJMe1209041 yet abiraterone is used in virtually all patients Copyright © 2012 Massachusetts Medical Society.

Tiotropium for Asthma — Promise and Caution Elisabeth H. Bel, M.D., Ph.D. Anticholinergic agents have been available for the linergic agents are less popular, probably because treatment of airways obstruction for many de­ of their slower onset of action as a reliever med- cades. For patients with chronic obstructive pul- ication and their generally inferior effect on lung monary disease (COPD), many practitioners believe function and symptoms, as compared with in- that these drugs have become the bronchodila- haled beta-agonists. tor of choice. For patients with asthma, anticho- Not surprisingly, long-acting beta-agonists

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