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Originally published as JCO Early Release 10.1200/JCO.2008.18.3145 on July 14 2008 © 2008 American Society of Clinical Oncology.
Prostate Cancer: Moving Forward by Reinventing the Wheel ... But This Time It Is Round
Cleveland Clinic Taussig Cancer Institute and Glickman Urological and Kidney Institute, Cleveland, OH The article by Attard et al1 in this issue of Journal of Clinical Oncology illustrates elegantly that we are gradually coming to understand the molecular basis of prostate cancer progression. The use of abiraterone acetate is predicated on the recognition that it can selectively block CYP17, a microsomal enzyme that catalyzes a series of reactions critical to nongonadal androgen biosynthesis. Furthermore, this study provides provocative preliminary evidence that this effect may be associated with expression of a TMPRSS2-ERG fusion protein that may be involved in the regulation of one of the pathways that drive the so-called hormone-resistant or refractory state.2 The important features in this article are the science and the clinical durability of response. All too often in the recent past, we have fallen prey to the trumpeting of statistically significant but clinically irrelevant outcomes, such as minor increments in progression-free survival, prostate-specific antigen dips, and other end points that really do not help patients who are in trouble. This study suggests that abiraterone acetate actually will be helpful to patients, and thus it should be taken seriously as a salvage therapeutic choice. This work is all the more exciting because other potentially useful second-line options, such as aminoglutethimide,3,4 LY 320236,5 and tesmilifene,6 which would give us added salvage options, have not been developed or maintained for the market for a range of reasons.
The thought that the hormone-refractory state is not absolute is really not new. Our colleagues in the world of breast cancer care have known this for years, and a quite standard therapeutic approach to that malignancy involves shifting back and forth between cytotoxic and endocrinologic manipulation, often with some success. The history of prostate cancer management has illustrated quite clearly that hormonal manipulation can be used repeatedly, and often with durable responses. Several published clinical trials have shown the potentially beneficial effects of aminoglutethimide,3,4 ketoconazole,7 estrogens,8 combined 5-
So what happens now? First, we must continue to extend our molecular studies to elucidate the mechanisms of hormone response and resistance, and to define more suitable targets for cytotoxic design or for the modification of cytotoxic therapy. Second, we need to involve our patients more often in well-designed and relevant clinical trials,11 analogous to what has been achieved for breast cancer. Third, we need to develop an altruistic mechanism, either with the support of the pharmaceutical industry, venture capitalists, and/or government mechanisms to allow the development of potentially useful orphan drugs in the domain of relapsed prostate cancer. Thus, if the perceived market share for a proven useful second-line agent is not sufficiently robust, one of these mechanisms might take over and provide the agent for the population of needful patients at reasonable cost, with vast savings to the community of prostate cancer patients and potentially high bang for the buck. Also of importance, we need to help the US Food and Drug Administration and other regulatory agencies to define optimal surrogate end points that translate into real patient benefit—the rhetoric surrounding minor impacts on outcome must be replaced by robust surrogates that translate into prolonged overall survival. Perhaps progression-free or disease-free survival will ultimately predict for sustained overall survival, and maybe a decrease of prostate-specific antigen from 6 to 3 ng/mL will eventually identify the patients who are likely to respond to new therapies. However, on the basis of the available published data and our own experience, this seems to be quite unlikely. Our recent data using the assessment of circulating tumor cells have suggested that outcomes in salvage therapy of prostate cancer can be predicted by this technology,12 but this information will have to be validated in randomized, well-designed trials before becoming a routine part of our management lexicon. Until useful surrogates are identified and validated, new agents must show improvements in overall survival and/or major improvement in symptom control for a minimum of 4 to 6 months in randomized clinical trials before we can claim real progress. Rhetoric must be replaced by careful and consistent clinical and translational science, taking advantage of our improved understanding of molecular mechanisms, and of our recognition that well-powered clinical trials, with robust end points, have underwritten most of the true clinical advances in modern oncology. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Manuscript writing: Derek Raghavan, Eric A. Klein Final approval of manuscript: Derek Raghavan, Eric A. Klein
NOTES published online ahead of print at www.jco.org on July 14, 2008 REFERENCES
1. 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 2. Holzbeierlein J, Lal P, LaTulippe E, et al: Gene expression analysis of prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am J Pathol 164:217-227, 2004 3. Harnett PR, Caterson ID, Raghavan D, et al: Aminoglutethimide in advanced prostatic carcinoma. Brit J Urol 59:323-327, 1987[Medline] 4. Ahmann FR, Crawford ED, Kreis W, et al: Adrenal steroid levels in men with prostatic carcinoma treated with aminoglutethimide plus hydrocortisone. Cancer Res 47:4736-4739, 1987 5. Eisenberger MA, Laufer M, Vogelzang NJ, et al: Phase I and clinical pharmacology of a type I and II, 5-alpha-reductase inhibitor (LY320236) in prostate cancer: Elevation of estradiol as possible mechanism of action. Urology 63:114-119, 2004[CrossRef][Medline] 6. Raghavan D, Brandes LJ, Klapp K, et al: Phase II trial of tesmilifene plus mitoxantrone and prednisone for hormone refractory prostate cancer: High subjective and objective response in patients with symptomatic metastases. J Urol 174:1808-1813, 2005[CrossRef][Medline] 7. Figg WD, Liu Y, Arlen P, et al: A randomized phase II trial of ketoconazole plus alendronate versus ketoconazole alone in patients with androgen independent prostate cancer and bone metastases. J Urol 173:790-796, 2005[CrossRef][Medline] 8. Droz JP, Kattan J, Bonnay M, et al: High-dose continuous-infusion fosfestrol in hormone-resistant prostate cancer. Cancer 71:1123-1130, 1993 (3 suppl)[CrossRef][Medline] 9. Kassouf W, Tanguay S, Aprikian AG: Nilutamide as second line hormone therapy for prostate cancer after hormone ablation fails. J Urol 169:1742-1744, 2003[CrossRef][Medline] 10. Raghavan D: Non-hormone chemotherapy for prostate cancer: Principles of treatment and application to the testing of new drugs. Semin Oncol 15:371-389, 1988[Medline] 11. Raghavan D: An essay on rearranging the deck chairs: What's wrong with the cancer trials system? Clin Cancer Res 12:1949-1950, 2006 12. DeBono JS, Scher HI, Montgomery B, et al: Circulating tumor cells predict survival benefit from treatment in metastatic prostate cancer. Clin Cancer Res (in press) Related Article
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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reductase inhibitors,
