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Originally published as JCO Early Release 10.1200/JCO.2009.25.3781 on February 16 2010 © 2010 American Society of Clinical Oncology.
Castration-Resistant Prostate Cancer—Hormone Therapy ReduxSouth Texas Accelerated Research Therapeutics, The START Center for Cancer Care, San Antonio, TX Androgen deprivation has been the mainstay in the treatment of advanced prostate cancer and is beyond a doubt the most effective therapeutic option; nearly all patients respond to initial androgen ablation therapy, and the duration of response is routinely measured in years, not months. Nonetheless, despite the effectiveness of hormone therapy, the majority of patients with advanced disease will develop evidence of progressive disease, heretofore termed androgen-independent or hormone-refractory prostate cancer. In contrast to the effectiveness of hormone therapy, the benefits from docetaxel, the current chemotherapy for hormone-resistant prostate cancer, are less satisfactory. Only one half of patients will have a prostate-specific antigen (PSA) response; patients experience considerable hematologic and nonhematologic toxicities; and in randomized studies, the improvement on overall survival is a modest 4 months better than that of our past chemotherapy standard, mitoxantrone.1–2 The development of effective second-line hormonal treatment therefore has been much desired, but the current agents have left much to be desired. Nonsteroidal antiandrogens induce a PSA response in some patients, but it is usually of short duration.3 Ketoconazole is used as an inhibitor of corticosteroid biosynthesis to achieve a medical adrenalectomy, but in most clinician's hands it is not a particularly effective therapy and is frequently quite toxic.4–7
It is within this context that some skepticism has greeted recent second-line hormone therapies, including the novel CYP17 inhibitor abiraterone or the novel androgen receptor inhibitor MDV3100. Abiraterone acetate, a CYP17 inhibitor prodrug, possesses potent 17
To further address this point, the sites of action of ketoconazole compared with abiraterone should be considered. Ketoconazole has multiple CYP inhibitory actions, and at the doses used for adrenalectomy, is a relatively weak inhibitor of CYP17, primarily inhibiting 11β hydroxylase, which results in inhibition of cortisol synthesis and requires the use of supplemental replacement hydrocortisone to prevent adrenal insufficiency. In contrast, abiraterone selectively inhibits 17 In this issue of Journal of Clinical Oncology, Ryan et al9 report a phase I study of orally administered abiraterone acetate. This article complements the results of four other published phase I dose escalation and activity studies that demonstrate the safety and potency of testosterone suppression, as well as the high level of antitumor activity, albeit as measured by PSA decline, of abiraterone acetate.8,10,11 The activity noted in chemically or surgically castrate, ketoconazole-naïve patients reported in all these studies implies that abiraterone acetate is certainly a highly active agent, but does not address the skeptic's concern of whether it is an improvement over the currently available and often-used ketoconazole. The new information from this study, that antitumor activity is nearly equivalent in both ketoconazole-pretreated and naïve populations, may well address this skepticism. Furthermore, Ryan et al9 demonstrated that the previously described toxicities of hypertension and hypokalemia associated with abiraterone acetate, driven in part by the aforementioned mineralocorticoid excess, could be abrogated by the use of low-dose prednisone. Based on the mechanism of action of abiraterone acetate, androgen biosynthesis inhibition, the clinical results from Ryan et al9 and other reports imply that many patients with prostate cancer have considerable sensitivity to peripherally produced, low-level androgen stimulation. The effectiveness of abiraterone acetate is being addressed in randomized controlled studies in chemotherapy-treated and chemotherapy-naïve patients. Nonetheless, several important issues remain to be addressed regarding the optimal dose of abiraterone acetate. Ryan et al9 indicate that improved absorption occurs in the fed state. However, their study was not designed to conclusively address the optimal timing of drug administration related to eating. A statistically significant difference in absorption in the fed state was reported in a previous report that supports the author's recommendation for fasting.10 Because patients outside of the controlled environment of a clinical study are apt to forget to fast before taking a chronically administered oral medication (despite education from doctors, nurses, and pharmacists), this may have importance for both optimal dose and safety. From the optimal dose standpoint, the data beg the question of whether lower doses could be equally effective as the recommended dose of 1,000 mg when administered to patients in the fed state. This represents an important commercial concern. From a safety issue, although no maximum tolerated dose was determined, and doses up to 2,000 mg daily have been tolerated by a limited number of patients in other studies, this does not completely remove the food effect as a safety concern. The risk remains that the fed state would elicit heretofore undocumented toxicities because of the attainment of higher (> 4-fold) abiraterone exposure.9 Also in this issue of JCO, Reid et al12 present the results of a single arm phase II study in prostate cancer patients who had received prior conventional castration and docetaxel therapy, while assessing antitumor activity and PSA progression on stringent PSA Working Group 1 criteria (PSAWG-1). When PSA response is defined by these criteria, a 50% response rate in the study population is encouraging. More significant, however, is that the duration of the response as defined by PSAWG-1 was a median of 24 weeks, with 25% of the patient population remaining on study 48 weeks or longer. If confirmed in randomized studies, this substantial increase in time to progression will be very meaningful to patients. Although corticosteroids were not mandated in this phase II study, the incidence of hypertension, hypokalemia, and peripheral edema from mineralocorticoid excess was of sufficient frequency to support the routine use of prednisone as recommended by Ryan et al. The unaddressed food effect, efficacy, and dosing issues notwithstanding, the encouraging results in Ryan et al9 and other studies of abiraterone acetate that demonstrate a high rate of durable PSA responses may change the current medical lexicon used to describe patients that do not respond to LHRH agonists or surgical castration: androgen-independent or hormone-refractory prostate cancer is neither androgen independent nor hormone refractory. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Anthony W. Tolcher, Johnson and Johnson (C) Stock Ownership: None Honoraria: None Research Funding: Anthony W. Tolcher, Centacor, Cougar Expert Testimony: None Other Remuneration: None
NOTES See accompanying articles on pages 1481, 1489, and 1496 REFERENCES
1. Petrylak DP, Tangen CM, Hussain MHA, et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351:1513–1520, 2004. 2. Tannock IF, de Wit R, Berry WR, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502–1512, 2004. 3. Schroder FH: Pure antiandrogens as monotherapy in prospective studies of prostatic carcinoma. Prog Clin Biol Res 359:93–103, 1990.[Medline] 4. Loose DS, Kan PB, Hirst MA, et al: Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes. J Clin Invest 71:1495–1499, 1983.[Medline] 5. Bok RA, Small EJ: The treatment of advanced prostate cancer with ketoconazole: Safety issues. Drug Saf 20:451–458, 1999.[CrossRef][Medline] 6. Harris KA, Weinberg V, Bok RA, et al: Low dose ketoconazole with replacement doses of hydrocortisone in patients with progressive androgen independent prostate cancer. J Urology 168:542–545, 2002.[CrossRef][Medline] 7. Small EJ, Halabi S, Dawson NA, et al: Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: A phase III trial (CALGB 9583). J Clin Oncol 22:1025–1033, 2004. 8. O'Donnell A, Judson I, Dowsett M, et al: Hormonal impact of the 17alpha-hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer. Br J Cancer 90:2317–2325, 2004.[Medline] 9. Ryan CJ, Smith MR, Fong L, et al: Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. J Clin Oncol 28:1481–1488, 2010. 10. Attard G, Reid AHM, Yap TA, et al: Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol 26:4563–4571, 2008. 11. Attard G, Reid AHM, 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 27:3742–3748, 2009. 12. Reid AHM, Attard G, Danila DC, et al: Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol 28:1489–1495, 2010.
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Copyright © 2010 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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-hydroxylase and C17,20-lyase inhibitory action and interferes with androgen biosynthesis, not only in the adrenal gland, but also in peripheral tissues of castrate and noncastrate men.
