Relationships between times to testosterone and prostate-specific antigen rises during the first off-treatment interval of intermittent androgen deprivation are prognostic for castration resistance in men with nonmetastatic prostate cancer

Abstract

Background: Intermittent androgen deprivation (IAD) represents an alternative to continuous AD with quality-of-life benefit and no evidence of inferior overall survival for nonmetastatic prostate cancer. Early markers of prognosis for men treated with IAD have not been described.

Patients and methods: Men with nonmetastatic prostate cancer were treated with 9 months of leuprolide and flutamide followed by a variable off-treatment interval; AD was resumed when prostate specific antigen (PSA) reached a prespecified value (1 ng/mL, radical prostatectomy; 4 ng/mL, intact prostate). Cycles were repeated until castration resistance (marking the advent of castration-resistant prostate cancer [CRPC]), defined as 2 PSA rises with testosterone (T) ≤ 50 ng/dL. Kinetics and relationships of PSA and T levels were evaluated, with a focus on times to rise in each level, during the first off-treatment interval. Associations with CRPC and prostate cancer mortality were estimated using Cox proportional hazards models controlling for age and Gleason score.

Results: Each 30-day increase in time to PSA rise was associated with a 21% reduction in the risk of developing CRPC (95% CI, 3%-36%; P = .02). Longer time (≥ 60 days) to PSA rise after rise to T > 50 ng/dL was associated with a 71% reduction in the risk of developing CRPC (95% CI, 92% reduction to 2% inflation; P = .05). Time to first T > 50 ng/dL and PSA doubling time were not prognostic for progression to CRPC. No time interval was prognostic for prostate cancer mortality.

Conclusion: During the first off-treatment interval of IAD, longer times to PSA rise overall and after T > 50 ng/dL were associated with reduced risk of developing CRPC.

Trial registration: ClinicalTrials.gov NCT00223665.

Keywords: Biochemical Recurrence; Castration-resistant; Overall Survival; Prognosis; Prostate-specific Antigen Kinetics.

Conflict of interest statement

CONFLICT OF INTEREST

Dr. Celestia S. Higano

Industry financial relationships over the past 3 years

Consultant for: AbbVie, Algeta, Amgen, Astellas, Bayer, BHR Pharma, Dendreon, Endo/Orion, Ferring, Fresenius, Genentech, Johnson&Johnson, Medivation, Novartis and Pfizer

Involvement in Research: Algeta, Amgen, Aragon, AstraZeneca, Bayer, Cougar Technology, Dendreon, Exelixis, Genentech, ImClone, Johnson&Johnson, Medivation, Millennium, Novartis, OncoGenex, Sanofi-Aventis and Teva Pharmaceuticals

Dr. Evan Y. Yu:

Industry financial relationships over the past 3 years:

Consultant for: Amgen, Astellas, Bayer, Dendreon, Janssen, Medivation, Millennium, Seattle Genetics

Involvement in Research: Agensys, Astellas, Astrazeneca, Bristol-Myers Squibb, Dendreon, GTx, Imclone, Janssen, Medivation, Novartis, OncoGeneX

Copyright © 2015 Elsevier Inc. All rights reserved.

Figures

Figure 1

Study schema illustrates one full cycle of IAD. Specific time points of interest are designated with arrows. Cycles are repeated until the development of castration-resistance or death.

Figure 2

Consort diagram displays rationale for selection of the 62 patients from the clinical trial for this exploratory analysis.

Figure 3

Kaplan-Meier curves illustrating time to castration-resistant prostate cancer (left panels) and prostate cancer mortality (right panels) predicted by four time intervals (panel rows) above (gray) and below (black) the marker median values or, for time from T >50 ng/dL to PSA rise,