Time interval to biochemical failure as a surrogate end point in locally advanced prostate cancer

Analysis of randomized trial NRG/ RTOG 9202

James J. Dignam, Daniel A. Hamstra, Herbert Lepor, David Grignon, Harmar Brereton, Adam Currey, Seth Rosenthal, Kenneth L. Zeitzer, Varagur M. Venkatesan, Eric M. Horwitz, Thomas M. Pisansky, Howard M. Sandler

Research output: Contribution to journalArticle

Abstract

BACKGROUND In prostate cancer, end points that reliably portend prognosis and treatment benefit (surrogate end points) can accelerate therapy development. Although surrogate end point candidates have been evaluated in the context of radiotherapy and short-term androgen deprivation (AD), potential surrogates under long-term (24 month) AD, a proven therapy in high-risk localized disease, have not been investigated. MATERIALS AND METHODS In the NRG/RTOG 9202 randomized trial (N = 1,520) of short-term AD (4 months) versus long-term AD (LTAD; 28 months), the time interval free of biochemical failure (IBF) was evaluated in relation to clinical end points of prostate cancer–specific survival (PCSS) and overall survival (OS). Survival modeling and landmark analysis methods were applied to evaluate LTAD benefit on IBF and clinical end points, association between IBF and clinical end points, and the mediating effect of IBF on LTAD clinical end point benefits. RESULTS LTAD was superior to short-term AD for both biochemical failure (BF) and the clinical end points. Men remaining free of BF for 3 years had relative risk reductions of 39% for OS and 73% for PCSS. Accounting for 3-year IBF status reduced the LTAD OS benefit from 12% (hazard ratio [HR], 0.88; 95% CI, 0.79 to 0.98) to 6% (HR, 0.94; 95% CI, 0.83 to 1.07). For PCSS, the LTAD benefit was reduced from 30% (HR, 0.70; 95% CI, 0.52 to 0.82) to 6% (HR, 0.94; 95% CI, 0.72 to 1.22). Among men with BF, by 3 years, 50% of subsequent deaths were attributed to prostate cancer, compared with 19% among men free of BF through 3 years. CONCLUSION The IBF satisfied surrogacy criteria and identified the benefit of LTAD on disease-specific survival and OS. The IBF may serve as a valid end point in clinical trials and may also aid in risk monitoring after initial treatment.

Original languageEnglish (US)
Pages (from-to)213-221
Number of pages9
JournalJournal of Clinical Oncology
Volume37
Issue number3
DOIs
StatePublished - Jan 20 2019
Externally publishedYes

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Prostatic Neoplasms
Biomarkers
Survival
Androgens
Prostate
Risk Reduction Behavior
Therapeutics
Radiotherapy
Clinical Trials

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Time interval to biochemical failure as a surrogate end point in locally advanced prostate cancer : Analysis of randomized trial NRG/ RTOG 9202. / Dignam, James J.; Hamstra, Daniel A.; Lepor, Herbert; Grignon, David; Brereton, Harmar; Currey, Adam; Rosenthal, Seth; Zeitzer, Kenneth L.; Venkatesan, Varagur M.; Horwitz, Eric M.; Pisansky, Thomas M.; Sandler, Howard M.

In: Journal of Clinical Oncology, Vol. 37, No. 3, 20.01.2019, p. 213-221.

Research output: Contribution to journalArticle

Dignam, JJ, Hamstra, DA, Lepor, H, Grignon, D, Brereton, H, Currey, A, Rosenthal, S, Zeitzer, KL, Venkatesan, VM, Horwitz, EM, Pisansky, TM & Sandler, HM 2019, 'Time interval to biochemical failure as a surrogate end point in locally advanced prostate cancer: Analysis of randomized trial NRG/ RTOG 9202', Journal of Clinical Oncology, vol. 37, no. 3, pp. 213-221. https://doi.org/10.1200/JCO.18.00154
Dignam, James J. ; Hamstra, Daniel A. ; Lepor, Herbert ; Grignon, David ; Brereton, Harmar ; Currey, Adam ; Rosenthal, Seth ; Zeitzer, Kenneth L. ; Venkatesan, Varagur M. ; Horwitz, Eric M. ; Pisansky, Thomas M. ; Sandler, Howard M. / Time interval to biochemical failure as a surrogate end point in locally advanced prostate cancer : Analysis of randomized trial NRG/ RTOG 9202. In: Journal of Clinical Oncology. 2019 ; Vol. 37, No. 3. pp. 213-221.
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abstract = "BACKGROUND In prostate cancer, end points that reliably portend prognosis and treatment benefit (surrogate end points) can accelerate therapy development. Although surrogate end point candidates have been evaluated in the context of radiotherapy and short-term androgen deprivation (AD), potential surrogates under long-term (24 month) AD, a proven therapy in high-risk localized disease, have not been investigated. MATERIALS AND METHODS In the NRG/RTOG 9202 randomized trial (N = 1,520) of short-term AD (4 months) versus long-term AD (LTAD; 28 months), the time interval free of biochemical failure (IBF) was evaluated in relation to clinical end points of prostate cancer–specific survival (PCSS) and overall survival (OS). Survival modeling and landmark analysis methods were applied to evaluate LTAD benefit on IBF and clinical end points, association between IBF and clinical end points, and the mediating effect of IBF on LTAD clinical end point benefits. RESULTS LTAD was superior to short-term AD for both biochemical failure (BF) and the clinical end points. Men remaining free of BF for 3 years had relative risk reductions of 39{\%} for OS and 73{\%} for PCSS. Accounting for 3-year IBF status reduced the LTAD OS benefit from 12{\%} (hazard ratio [HR], 0.88; 95{\%} CI, 0.79 to 0.98) to 6{\%} (HR, 0.94; 95{\%} CI, 0.83 to 1.07). For PCSS, the LTAD benefit was reduced from 30{\%} (HR, 0.70; 95{\%} CI, 0.52 to 0.82) to 6{\%} (HR, 0.94; 95{\%} CI, 0.72 to 1.22). Among men with BF, by 3 years, 50{\%} of subsequent deaths were attributed to prostate cancer, compared with 19{\%} among men free of BF through 3 years. CONCLUSION The IBF satisfied surrogacy criteria and identified the benefit of LTAD on disease-specific survival and OS. The IBF may serve as a valid end point in clinical trials and may also aid in risk monitoring after initial treatment.",
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T1 - Time interval to biochemical failure as a surrogate end point in locally advanced prostate cancer

T2 - Analysis of randomized trial NRG/ RTOG 9202

AU - Dignam, James J.

AU - Hamstra, Daniel A.

AU - Lepor, Herbert

AU - Grignon, David

AU - Brereton, Harmar

AU - Currey, Adam

AU - Rosenthal, Seth

AU - Zeitzer, Kenneth L.

AU - Venkatesan, Varagur M.

AU - Horwitz, Eric M.

AU - Pisansky, Thomas M.

AU - Sandler, Howard M.

PY - 2019/1/20

Y1 - 2019/1/20

N2 - BACKGROUND In prostate cancer, end points that reliably portend prognosis and treatment benefit (surrogate end points) can accelerate therapy development. Although surrogate end point candidates have been evaluated in the context of radiotherapy and short-term androgen deprivation (AD), potential surrogates under long-term (24 month) AD, a proven therapy in high-risk localized disease, have not been investigated. MATERIALS AND METHODS In the NRG/RTOG 9202 randomized trial (N = 1,520) of short-term AD (4 months) versus long-term AD (LTAD; 28 months), the time interval free of biochemical failure (IBF) was evaluated in relation to clinical end points of prostate cancer–specific survival (PCSS) and overall survival (OS). Survival modeling and landmark analysis methods were applied to evaluate LTAD benefit on IBF and clinical end points, association between IBF and clinical end points, and the mediating effect of IBF on LTAD clinical end point benefits. RESULTS LTAD was superior to short-term AD for both biochemical failure (BF) and the clinical end points. Men remaining free of BF for 3 years had relative risk reductions of 39% for OS and 73% for PCSS. Accounting for 3-year IBF status reduced the LTAD OS benefit from 12% (hazard ratio [HR], 0.88; 95% CI, 0.79 to 0.98) to 6% (HR, 0.94; 95% CI, 0.83 to 1.07). For PCSS, the LTAD benefit was reduced from 30% (HR, 0.70; 95% CI, 0.52 to 0.82) to 6% (HR, 0.94; 95% CI, 0.72 to 1.22). Among men with BF, by 3 years, 50% of subsequent deaths were attributed to prostate cancer, compared with 19% among men free of BF through 3 years. CONCLUSION The IBF satisfied surrogacy criteria and identified the benefit of LTAD on disease-specific survival and OS. The IBF may serve as a valid end point in clinical trials and may also aid in risk monitoring after initial treatment.

AB - BACKGROUND In prostate cancer, end points that reliably portend prognosis and treatment benefit (surrogate end points) can accelerate therapy development. Although surrogate end point candidates have been evaluated in the context of radiotherapy and short-term androgen deprivation (AD), potential surrogates under long-term (24 month) AD, a proven therapy in high-risk localized disease, have not been investigated. MATERIALS AND METHODS In the NRG/RTOG 9202 randomized trial (N = 1,520) of short-term AD (4 months) versus long-term AD (LTAD; 28 months), the time interval free of biochemical failure (IBF) was evaluated in relation to clinical end points of prostate cancer–specific survival (PCSS) and overall survival (OS). Survival modeling and landmark analysis methods were applied to evaluate LTAD benefit on IBF and clinical end points, association between IBF and clinical end points, and the mediating effect of IBF on LTAD clinical end point benefits. RESULTS LTAD was superior to short-term AD for both biochemical failure (BF) and the clinical end points. Men remaining free of BF for 3 years had relative risk reductions of 39% for OS and 73% for PCSS. Accounting for 3-year IBF status reduced the LTAD OS benefit from 12% (hazard ratio [HR], 0.88; 95% CI, 0.79 to 0.98) to 6% (HR, 0.94; 95% CI, 0.83 to 1.07). For PCSS, the LTAD benefit was reduced from 30% (HR, 0.70; 95% CI, 0.52 to 0.82) to 6% (HR, 0.94; 95% CI, 0.72 to 1.22). Among men with BF, by 3 years, 50% of subsequent deaths were attributed to prostate cancer, compared with 19% among men free of BF through 3 years. CONCLUSION The IBF satisfied surrogacy criteria and identified the benefit of LTAD on disease-specific survival and OS. The IBF may serve as a valid end point in clinical trials and may also aid in risk monitoring after initial treatment.

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