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Journal of Clinical Oncology, Vol 26, No 21 (July 20), 2008: pp. 3647-3648 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.17.1140
Trial Design for Metastatic Castration-Resistant Prostate CancerU.S. Oncology Research, Houston, TX To the Editor: While the recommendations of the (Prostate Cancer Working Group 2 (PCWG2) clearly represent a step in the right direction, we raise several issues with their article.1 The PCWG2 recommended the elimination of a universal mandatory trial of antiandrogen withdrawal (AAWD) for 4 to 6 weeks in patients with castration-resistant prostate cancer (CRPC). It was, however, suggested that subsets of patients (those on initial combined androgen blockade for a prolonged period of time, or who have responded to adding an antiandrogen) should continue to undergo AAWD. However, most trials also mandate 4 weeks off prior megestrol, ketoconazole, aminoglutethimide, or systemic steroids. No evidence exists for a withdrawal response or a delayed response after discontinuation of these hormone agents, and therefore a 4-week washout period is probably not warranted for all of these agents. In addition, even among appropriately selected patients, many will progress rapidly within 1 to 3 weeks of AAWD and it is impractical to wait an additional 3 to 5 weeks before systemic therapy on a clinical trial. It is also appropriate to restate that AAWD has not been demonstrated to enhance survival, and is seldom employed in the setting of advanced breast cancer despite some evidence of activity.2,3 Therefore, in order to allay patient anxiety and enhance clinical trial accrual, investigator judgment and flexibility in the duration of antiandrogen withdrawal are probably necessary.
While the PCWG2 recommends recording the prostate-specific antigen (PSA) nadir with prior hormone therapy, no specific recommendations are enunciated regarding whether this covariate should be used to stratify patients with CRPC entering clinical trials. Data in the setting of metastatic prostate cancer on hormone therapy have revealed the powerful prognostic value of the PSA nadir.4,5 The median survival was 13 months for patients with a PSA nadir higher than 4 ng/mL, 44 months for patients with PSA nadir 0.2 to 4 ng/mL, and 75 months for patients with PSA nadir
The PCWG2 also recommends against reporting 50% or 30% PSA response rates but favors reporting waterfall plots of any change in PSA over 12 weeks. While we recognize that a validated PSA based surrogate has not been identified, the abandonment of reporting PSA response rates and employment of waterfall plots is also not based on validated data.7 A retrospective study of the Southwest Oncology Group 9916 trial analyzed PSA velocity and PSA declines ranging from 5% to 90% within 3 months for surrogacy.8 The optimal biochemical surrogate found in this study was a 30% PSA decline. Data from the TAX327 trial were employed to analyze PSA declines ranging from 0% to 90%, PSA velocity, and pain response as intermediate surrogate end points. A PSA decline of The PCWG2 discourages employing changes in PSA-DT or slope as a primary end point. However, this contradicts their general recommendation of defining objectives in relation to the mechanism of action of an agent. For example, some cytostatic agents may yield improved outcomes by retarding progression (eg, vaccines, antiangiogeneic agents), or may even mechanistically require some progression to yield activity (eg, demethylating agents). Indeed, in a retrospective analysis of patients with CRPC receiving GVAX vaccine (Cell Genesys Inc, South San Francisco, CA), reduced post-treatment PSA slopes was associated with longer survival compared with those with a stable or increasing PSA slope.10 While a randomized trial of novel agents with a clinical primary end point in this setting is desirable, in the era of resource constraints and given the poor validity of progression-free survival in a nonrandomized straight phase II trial, a mechanistic case may be made for changes in PSA-DT/slope to provide a signal of activity in straight phase II trials of some cytostatic agents. 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: Thomas E. Hutson, Bayer/Onyx (C), Pfizer (C), Dendreon (C), Sanofi-aventis (C) Stock Ownership: None Honoraria: Guru Sonpavde, Pfizer, Novartis; Mark T. Fleming, Sanofi-aventis, Pfizer; Thomas E. Hutson, Bayer/Onyx, Genentech, Sanofi-aventis, Amgen, Pfizer; Matthew D. Galsky, Pfizer Research Funding: Guru Sonpavde, Pfizer, Bristol-Myers Squibb Co, Eli Lilly & Co, AstraZeneca, Cytogen; Thomas E. Hutson, Bayer/Onyx, GlaxoSmithKline, Pfizer Expert Testimony: None Other Remuneration: None REFERENCES
1. Scher HI, Halabi S, Tannock I, et al: Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: Recommendations of the prostate cancer clinical trials working group. J Clin Oncol 26:1148-1159, 2008 2. Cigler T, Goss PE: Aromatase inhibitor withdrawal response in metastatic breast cancer. J Clin Oncol 24:1955-1956, 2006 3. Howell A, Dodwell DJ, Anderson H, et al: Response after withdrawal of tamoxifen and progestogens in advanced breast cancer. Ann Oncol 3:611-617, 1992 4. Hussain M, Tangen CM, Higano C, et al: Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: Data from Southwest Oncology Group Trial 9346 (INT-0162). J Clin Oncol 24:3984-3990, 2006 5. Stewart AJ, Scher HI, Chen MH, et al: Prostate-specific antigen nadir and cancer-specific mortality following hormonal therapy for prostate-specific antigen failure. J Clin Oncol 23:6556-6560, 2005 6. Armstrong AJ, Garrett-Mayer E, Yang YC, et al: A contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: A TAX327 study analysis. Clin Cancer Res 13:6396-6403, 2007 7. Fleming MT, Morris MJ, Heller G, et al: Post-therapy changes in PSA as an outcome measure in prostate cancer clinical trials. Nat Clin Pract Oncol 3:658-667, 2006[CrossRef][Medline] 8. Petrylak DP, Ankerst DP, Joang CS, et al: Evaluation of prostate-specific antigen declines for surrogacy in patients treated on SWOG 99-16. J Natl Cancer Inst 98:516-521, 2006 9. Armstrong AJ, Garrett-Mayer E, Yang YC, et al: Prostate-specific antigen and pain surrogacy analysis in metastatic hormone-refractory prostate cancer. J Clin Oncol 25:3965-3970, 2007 10. Small EJ, Sacks N, Nemunaitis J, et al: Granulocyte macrophage colony-stimulating factor-secreting allogeneic cellular immunotherapy for hormone-refractory prostate cancer. Clin Cancer Res 13:3883-3891, 2007
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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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0.2 ng/mL.
30% within 3 months of chemotherapy initiation had the highest degree of surrogacy for overall survival.
