Free Testosterone During Androgen Deprivation Therapy Predicts Castration‐Resistant Progression Better Than Total Testosterone

Regis, Lucas; Planas, Jacques; Carles, Joan; Maldonado, X.; Comas, Inma; Ferrer, Roser; Moróte, Juan

doi:10.1002/pros.23256

Cited by 10 publications

(17 citation statements)

References 28 publications

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“…In this study, we developed the first mechanistic population-based disease progression model that allowed us to investigate such complex relationship. Baseline PSA and HGB were identified as important covariates on PSA kinetics, consistent with previous findings that these two covariates played an important role in the development of castration resistance [8,9,12]. However, these two covariates affected different model parameters and hence had very different results on PSA kinetics and biochemical progression.…”

Section: Plos Onesupporting

confidence: 86%

“…In addition, laboratory measurements including those that have been reported to affect clinical outcomes in castration-resistant PCa were extracted for each patient. These laboratory measurements included aspartate transaminase (AST), alanine transaminase (ALT), serum creatinine (SCR), alkaline phosphatase (ALP), albumin (ALB) and hemoglobin (HGB) [8,9,[25][26][27][28][29][30][31][32][33].…”

Section: Study Subjectsmentioning

confidence: 99%

“…Most of these predictive models were developed using multivariate analysis that provides very little biological insight on the relationship between identified predictors and disease progression [8][9][10][11][12]. Several PSA kinetic parameters such as time to PSA nadir and PSA nadir level have been shown to be significant predictors of disease progression for PCa patients receiving ADT [9][10][11]. However, the complex quantitative relationship between clinical predictors and PSA kinetics and disease progression in ADT-treated PCa patients remains largely unknown.…”

Section: Plos Onementioning

confidence: 99%

“…Nevertheless, retrospective nature of this study suggested that our findings will need to be validated in prospective clinical studies. Second, some clinical measures that assess disease severity and/or metastasis spread, including metastasis stage, the Gleason score, Eastern Cooperative Oncology Group (ECOG) performance status and the Soloway score, were shown to be predictive of biomedical progression [9,11,12]. However, they were not available in the medical claims database, and therefore they could not be evaluated for their importance in our model.…”

Section: Plos Onementioning

confidence: 99%

“…However, the majority of patients eventually progress to a castration-resistant state, and it was estimated that the response to ADT typically lasts 14 to 20 months in metastatic PCa [5,6], and the duration of response to ADT is variable among patients [7]. A few studies have examined clinical factors that predict the time to castration resistance for patients on ADT [8][9][10][11][12], but the detailed timedependent profile of tumor regression and/or growth in patients with hormone-sensitive PCa on medical ADT has never been fully characterized.…”

Section: Introductionmentioning

confidence: 99%

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Using medical claims database to develop a population disease progression model for leuprorelin-treated subjects with hormone-sensitive prostate cancer

et al. 2020

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Androgen deprivation therapy (ADT) is a widely used treatment for patients with hormonesensitive prostate cancer (PCa). However, duration of treatment response varies, and most patients eventually experience disease progression despite treatment. Leuprorelin is a luteinizing hormone-releasing hormone (LHRH) agonist, a commonly used form of ADT. Prostate-specific antigen (PSA) is a biomarker for monitoring disease progression and predicting treatment response and survival in PCa. However, time-dependent profile of tumor regression and growth in patients with hormone-sensitive PCa on ADT has never been fully characterized. In this analysis, nationwide medical claims database provided by Humana from 2007 to 2011 was used to construct a population-based disease progression model for patients with hormone-sensitive PCa on leuprorelin. Data were analyzed by nonlinear mixed effects modeling utilizing Monte Carlo Parametric Expectation Maximization (MCPEM) method in NONMEM. Covariate selection was performed using a modified Wald's approximation method with backward elimination (WAM-BE) proposed by our group. 1113 PSA observations from 264 subjects with malignant PCa were used for model development. PSA kinetics were well described by the final covariate model. Model parameters were well estimated, but large between-patient variability was observed. Hemoglobin significantly affected proportion of drug-resistant cells in the original tumor, while baseline PSA and antiandrogen use significantly affected treatment effect on drug-sensitive PCa cells (Ds). Population estimate of Ds was 3.78 x 10 −2 day-1. Population estimates of growth rates for drugsensitive (Gs) and drug-resistant PCa cells (G R) were 1.96 x 10 −3 and 6.54 x 10 −4 day-1 , corresponding to a PSA doubling time of 354 and 1060 days, respectively. Proportion of the original PCa cells inherently resistant to treatment was estimated to be 1.94%. Application of population-based disease progression model to clinical data allowed characterization of tumor resistant patterns and growth/regression rates that enhances our understanding of how PCa responds to ADT.

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Section: Plos Onesupporting

confidence: 86%

Section: Study Subjectsmentioning

confidence: 99%

Section: Plos Onementioning

confidence: 99%

Section: Plos Onementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Using medical claims database to develop a population disease progression model for leuprorelin-treated subjects with hormone-sensitive prostate cancer

et al. 2020

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Testosterone Reduction of ≥ 480 ng/dL Predicts Favorable Prognosis of Japanese Men With Advanced Prostate Cancer Treated With Androgen-Deprivation Therapy

Yamamoto

Sakamoto

et al. 2017

Clinical Genitourinary Cancer

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Estetrol Cotreatment of Androgen Deprivation Therapy in Infiltrating or Metastatic, Castration-sensitive Prostate Cancer: A Randomized, Double-blind, Phase II Trial (PCombi)

Bennink

Moorselaar

Crawford

et al. 2021

European Urology Open Science

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Background Androgen deprivation therapy (ADT) for prostate cancer with luteinizing hormone-releasing hormone (LHRH) agonists can be improved. Objective To assess safety, the frequency and severity of hot flushes (HFs), bone health, and antitumor effects of high-dose estetrol (HDE4) when combined with ADT. Design, setting and participants A phase II, double-blind, randomized, placebo-controlled study was conducted in advanced prostate cancer patients requiring ADT (the PCombi study). Intervention Patients receiving LHRH agonist treatment were randomized 2:1 to 40 mg HDE4 ( n = 41) or placebo ( n = 21) cotreatment for 24 wk. Outcome measurements and statistical analysis Coprimary endpoints were frequency/severity of HFs and levels of total and free testosterone (T). Secondary endpoints included assessments of bone metabolism (osteocalcin and type I collagen telopeptide [CTX1]), prostate-specific antigen (PSA), and follicle-stimulating hormone (FSH). Efficacy analysis was based on the selected per-protocol (PP) population. Results and limitations Of 62 patients included in the study, 57 were suitable for a PP analysis (37 HDE4; 20 placebo). No E4-related serious cardiovascular adverse events occurred at 24 wk. Weekly HFs were reported by 13.5% of patients with HDE4 and 60.0% with placebo ( p < 0.001). Daily HFs occurred in 5.9% versus 55%. Bone turnover parameters decreased significantly with HDE4 ( p < 0.0001). Total and free T decreased earlier ( p < 0.05), and free T was suppressed further ( p < 0.05). PSA suppression was more profound and earlier ( p < 0.005). FSH levels were suppressed by 98% versus 57% ( p < 0.0001). Estrogenic side effects were nipple sensitivity (34%) and gynecomastia (17%). Conclusions HDE4 cotreatment of ADT patients with advanced prostate cancer was well tolerated, and no treatment-related cardiovascular adverse events were observed at 24 wk. HFs and bone turnover were substantially reduced. Suppression of free T, PSA, and FSH was more rapid and profound, suggesting enhanced disease control by HDE4 cotreatment. Larger and longer-lasting studies are needed to confirm the results of the study reported here. Patient summary Cotreatment of androgen deprivation therapy with high-dose estetrol in advanced prostate cancer patients results in fewer occurrences of hot flushes, bone protection, and other antitumor benefits. Nipple sensitivity and gynecomastia may occur as side effects.

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Free Testosterone During Androgen Deprivation Therapy Predicts Castration‐Resistant Progression Better Than Total Testosterone

Abstract: Free testosterone at 6 months of LHRH agonist treatment seems to be a better surrogate than total testosterone to predict castration resistance in no metastatic prostate cancer patients. Prostate 77:114-120, 2017. © 2016 Wiley Periodicals, Inc.

Cited by 10 publications

References 28 publications

Using medical claims database to develop a population disease progression model for leuprorelin-treated subjects with hormone-sensitive prostate cancer

Using medical claims database to develop a population disease progression model for leuprorelin-treated subjects with hormone-sensitive prostate cancer

Testosterone Reduction of ≥ 480 ng/dL Predicts Favorable Prognosis of Japanese Men With Advanced Prostate Cancer Treated With Androgen-Deprivation Therapy

Estetrol Cotreatment of Androgen Deprivation Therapy in Infiltrating or Metastatic, Castration-sensitive Prostate Cancer: A Randomized, Double-blind, Phase II Trial (PCombi)

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