Early Androgen Deprivation Therapy Research Articles

Abstract 6023: Plasma methylome landscape across the spectrum of prostate cancer progression, and differentially methylated region (DMR) based biomarkers of hormonal therapy failure in metastatic hormone-sensitive prostate cancer

Abstract Background: DNA silencing of gene expression can affect tumorigenesis, treatment outcomes and prognosis. Epigenetic silencing of tumor suppressor genes in prostate cancer detected in plasma at different stages of progression and its effect on clinical outcomes has not been determined. In a cohort study across different stages of prostate cancer (PC) progression, we performed plasma cell-free DNA (cfDNA)-based epigenomic profiling for determining the landscape of methylation and Differentially Methylated Region (DMR) classifiers and the potential impact on clinical outcomes in metastatic hormone-sensitive prostate cancer (mHSPC) state. Methods: Plasma was collected prospectively in a longitudinal cohort study of 108 PC patients (pts) of which 24 had non-metastatic Local PC; 28 had mHSPC; 56 had mCRPC. cfDNA was used for enzymatic methylation sequencing (EM-seq) of a targeted panel of genes (N=441) implicated in prostate cancer biology. Methylation status at CpG islands of these genes were examined using Twist targeted cfDNA methylation assay. The Bismark program was used for methylation calls. Temporal trends of differentially methylated regions (DMRs) were identified in different states of progression by comparing the methylation status of target genes in localized PC, mHSPC and mCRPC states using a False Discovery Rate (FDR-q-value) of 0.2 or less. DMRs uniquely associated with mHSPC state were identified and determination of genes with DMRs in pts experiencing early failure of androgen deprivation therapy (ADT)-based therapies was performed. Early failure was defined as progression on ADT within 12 months. Results: We identified 304/441 genes that were differentially methylated between localized PC and advanced PC (mHSPC and mCRPC) (FDR<0.2), of which 237 genes differed between mHSPC and mCRPC (p<0.05) states. mHSPC pts were serially profiles before and after 3 months of ADT-based therapies. All 28 pts experienced a PSA response at 3-months and 112/237 genes showed significant change in methylation status in these serial samples taken before/after 3 months of ADT-based therapies. The median follow up of the cohort was 18 months (range 10-24). 6/28 mHSPC pts experienced early ADT failure (<12 months; median 10 months). 8/112 genes were significantly associated with early failures and included DMRs in RB1, FOXA1, SOX11. GSC, ALDH1L1, SCGB3A1, FLT4, and PTPRN2. Conclusions. A targeted cfDNA plasma liquid-biopsy based epigenomic profiling of PC cancer related genes was able to capture significant differences in DMRs across different states of cancer progression. Candidate differentially expressed CpG methylome gene biomarkers detected in plasma also identified biomarkers associated with early ADT-based treatment failure in mHSPC. Citation Format: Manish Kohli, Jodie Wong, Yijun Tian, Amir Bitaraf, Claire Hanson, Matt Larsen, Jennifer Lloyd, Julia Batten, Neeraj Agarwal, Umang Swami, Benjamin Maughan, Sumati Gupta, Jonathan Tward. Plasma methylome landscape across the spectrum of prostate cancer progression, and differentially methylated region (DMR) based biomarkers of hormonal therapy failure in metastatic hormone-sensitive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6023.

MP20-06 ATORVASTATIN WITH DEGARELIX MODULATES TUMOR PROLIFERATION AND THE PROSTATE TUMOR IMMUNE ENVIRONMENT IN A Myc-CaP/AS MURINE MODEL

You have accessJournal of UrologyCME1 Apr 2023MP20-06 ATORVASTATIN WITH DEGARELIX MODULATES TUMOR PROLIFERATION AND THE PROSTATE TUMOR IMMUNE ENVIRONMENT IN A Myc-CaP/AS MURINE MODEL Ashanda Esdaille, Bing Yang, Tanaya Purohit, Kayla Bahr, Ali Ghasemzadeh, Dagna Sheerar, Douglas McNeel, and David Jarrard Ashanda EsdailleAshanda Esdaille More articles by this author , Bing YangBing Yang More articles by this author , Tanaya PurohitTanaya Purohit More articles by this author , Kayla BahrKayla Bahr More articles by this author , Ali GhasemzadehAli Ghasemzadeh More articles by this author , Dagna SheerarDagna Sheerar More articles by this author , Douglas McNeelDouglas McNeel More articles by this author , and David JarrardDavid Jarrard More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003245.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Androgen deprivation therapy (ADT) exerts immunomodulatory effects and induces a unique phenotypic response that accumulating data suggests may be improved with the addition of standard medications. Prior studies have shown that ADT and metformin or statins improves oncologic outcomes versus ADT alone. We hypothesize that these outcomes may be due to the effects of statins and ADT in immune and prostate tumor modulation. We aim to investigate whether Atorvastatin±ADT alters tumor growth, proliferation, apoptosis and the immune infiltrate within myc-CaP/AS murine models. METHODS: FVB/NJ, immunocompetent mice were injected subcutaneously with 1x106 Myc-CaP/AS cells. Treatment was initiated at an average tumor volume of 400mm3. Groups were randomized into short term (5 days post ADT) and long term (10 days post) for a total of 8 mice per group per time period. Mice were injected i.p. with: 1) 5µg/g Atorvastatin, q2 days x 3 doses OR q2 days x 5 doses AND/OR 2) Degarelix 25µg/g x 1 dose OR 3) PBS i.p. for controls. Immunohistochemical staining, followed by flow cytometry, was performed using single cell suspensions of harvested tumors. Western blots were performed to assess expression of PCNA and CC3. RESULTS: ADT + Atorvastatin treated tumors had the greatest decrease in volume (Figure 1). Tumor volume differences were present between post-treatment Atorvastatin vs control (p=0.029) and post-treatment Degarelix +Atorvastatin vs control (p=0.018). On flow cytometric analysis, Atorvastatin-treated tumors had the greatest CD8 T-cell expansion over time. MDSC expression decreased significantly over time for ADT and ADT + Atorvastatin-treated tumors. Early ADT and ADT + Atorvastatin decreased tumor proliferation and late Atorvastatin increased apoptosis in myc-CaP/AS tumors. CONCLUSIONS: Atorvastatin+ADT combination therapy decreased tumor volume and tumor proliferation when compared to ADT or statin drug alone. Atorvastatin alone increased CD8 T-cell presence, important for cell death, and in combination with ADT, decreased MDSC expression, which impedes cancer cell death. Demonstrating synergy between androgen deprivation and immunomodulatory agents has to potential to shift the treatment paradigm in patients with high-risk prostate cancer. Source of Funding: AUA/UCF Grant# 017-822959 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e277 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ashanda Esdaille More articles by this author Bing Yang More articles by this author Tanaya Purohit More articles by this author Kayla Bahr More articles by this author Ali Ghasemzadeh More articles by this author Dagna Sheerar More articles by this author Douglas McNeel More articles by this author David Jarrard More articles by this author Expand All Advertisement PDF downloadLoading ...

P072 - Advanced age and early androgen deprivation therapy increase survival at different stages of the treatment in castration resistant prostate cancer patients

P072 - Advanced age and early androgen deprivation therapy increase survival at different stages of the treatment in castration resistant prostate cancer patients

MP32-05 CONTEMPORARY HISTORY OF PROGRESSION FOLLOWING ANDROGEN DEPRIVATION THERAPY FOR BIOCHEMICAL RECURRENCE AFTER RADICAL PROSTATECTOMY

You have accessJournal of UrologyProstate Cancer: Epidemiology & Natural History II (MP32)1 Sep 2021MP32-05 CONTEMPORARY HISTORY OF PROGRESSION FOLLOWING ANDROGEN DEPRIVATION THERAPY FOR BIOCHEMICAL RECURRENCE AFTER RADICAL PROSTATECTOMY Timothy Daskivich, Shannon Stock, William Aronson, Martha Terris, Zachary Klaassen, Christopher Kane, Christopher Amling, Matthew Cooperberg, and Stephen Freedland Timothy DaskivichTimothy Daskivich More articles by this author , Shannon StockShannon Stock More articles by this author , William AronsonWilliam Aronson More articles by this author , Martha TerrisMartha Terris More articles by this author , Zachary KlaassenZachary Klaassen More articles by this author , Christopher KaneChristopher Kane More articles by this author , Christopher AmlingChristopher Amling More articles by this author , Matthew CooperbergMatthew Cooperberg More articles by this author , and Stephen FreedlandStephen Freedland More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002036.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Men with biochemical recurrence (BCR) after radical prostatectomy (RP) who are not treated with early androgen deprivation therapy (ADT) have a median time to metastasis of 8 years based on natural history data from the pre-2000s era. We sought to characterize risks of castration-resistant prostate cancer (CRPC) and metastasis in a contemporary VA cohort treated with early ADT for BCR after RP. METHODS: We analyzed 810 men with nonmetastatic prostate cancer starting ADT for non-metastatic BCR after RP from 1988–2017 in the VA SEARCH database. Multivariable Cox proportional hazards analysis was used to identify predictors of CRPC and metastasis. Kaplan-Meier analysis was used to quantify risk across key predictors. RESULTS: Median follow up was 5.7 years (IQR 3.1,9.6) after ADT. Median PSA at ADT was 1.4 ng/mL (IQR 0.3, 5.0). Across all men, 8-year risk of metastasis was 22%. In multivariable models, higher pre-ADT PSA (HR 1.78, p <0.001), seminal vesicle invasion (HR 1.69, p=0.004), shorter pre-ADT PSA doubling time (PSADT) (p=0.002), higher pathologic grade group (GG) (p=0.01), and higher BMI (p=0.007) were associated with higher risk of metastasis. 8-year risk of metastasis among those at highest risk with pre-ADT PSADT <3 mos, pathological GG5, or pre-ADT PSA of ≥10 was 27%, 32%, and 41%, respectively (Figure). Across all men, 8-year risk of CRPC was 25%. In multivariable models, higher pre-ADT PSA (HR 1.81, p <0.001), seminal vesicle invasion (HR 1.84, p <0.001), shorter pre-ADT PSADT (p <0.001), higher pathological GG (p=0.008), higher BMI (p=0.003), radiation before ADT (HR 1.62, p=0.01) and longer time from BCR to ADT (HR 1.01, p=0.01) were associated with higher risk of CRPC. Positive surgical margins (HR 0.69, p=0.03) and earlier year of ADT (HR 0.94, p=0.002) were associated with lower risk of CRPC. 8-year risk of CRPC among those at highest risk with pre-ADT PSADT <3 mos, pathological GG5, or pre-ADT PSA of ≥10 was 32%, 34%, and 50%, respectively. CONCLUSIONS: Risks of metastasis and CRPC after ADT for post-RP BCR are lower than in the historical literature for men not treated with ADT, with only 25% progressing to CRPC and 22% to metastasis after 8 years. Even in high risk subgroups, risks of metastases or CRPC at 8-years were <50%, demonstrating the long natural history of early ADT. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e566-e566 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Timothy Daskivich More articles by this author Shannon Stock More articles by this author William Aronson More articles by this author Martha Terris More articles by this author Zachary Klaassen More articles by this author Christopher Kane More articles by this author Christopher Amling More articles by this author Matthew Cooperberg More articles by this author Stephen Freedland More articles by this author Expand All Advertisement Loading ...

Diagnosis of advanced prostate cancer at the community level in Rwanda.

Prostate cancer is the second most common cancer in men and sixth leading cause of mortality. If not recognized early, patients with advanced prostate cancer can experience debilitating complications which can otherwise be prevented by early androgen deprivation therapy. This research intends to define clear diagnostic tools that will guide practitioners in the rural community setting toward early management of advanced prostate cancer. We conducted a cross-sectional observational study at three referral hospitals in Kigali, Rwanda on patients who presented with clinical suspicion of advanced prostate cancer over a period of 6months. All patients underwent prostate biopsy as well as metastatic work up (CT or MRI), for those who were eligible. Statistical analysis was done using STATA 14.2. 114 patients were included in the study. The median age was 70years (interquartile range: 65-79years). In total 14 (12.3%) patients were found to have benign disease, while 100 (87.7%) patients were found to have cancer. Among those who had cancer, 85 (85%) had advanced prostate cancer. 110/114 (96.5%) were symptomatic at presentation. Common presenting symptoms were lower urinary tract symptoms (80.7%), back pain (54.4%), and urinary retention (36.8%). Abnormal digital rectal examination (DRE) was a strong risk factor for both cancer and advanced disease. Prostate cancer was found in 92.2% of those with abnormal DRE compared to 41.7% in those with normal DRE (p = 0.001). Also, cancer was found in 96.1% of those with multinodular prostate on DRE (p = 0.02) and had high odds (OR 14.6; CI 3.41-62.25) of having advanced prostate cancer (p < 0.001). The mean (± SD) PSA was 643.3 ± 1829.8ng/ml and the median (range) was 100ng/ml (9.05-10,000ng/ml) for the whole study population. All patients with prostatic-specific antigen (PSA) of 100ng/ml or above had advanced prostate cancer. The results show that there is a significant correlation between clinical findings and advanced prostate cancer. All patients with abnormal DRE and PSA above 100ng/ml had advanced prostate cancer. Diagnosis of advanced prostate cancer is possible at the community level if PSA testing is utilized and practitioners are well trained.

Definition and Impact on Oncologic Outcomes of Persistently Elevated Prostate-specific Antigen After Salvage Lymph Node Dissection for Node-only Recurrent Prostate Cancer After Radical Prostatectomy: Clinical Implications for Multimodal Therapy

BackgroundThe optimal definition and prognostic significance of persistently elevated prostate-specific antigen (PSA) after salvage lymph node dissection (sLND) for node-only recurrent prostate cancer (PCa) remain unknown. ObjectiveTo assess the definition and clinical implications of persistently elevated PSA after sLND for node-only recurrent PCa after radical prostatectomy. Design, setting, and participantsThe study included 579 patients treated with sLND at 11 high-volume centers between 2000 and 2016. Outcome measurements and statistical analysisWe assessed the linear relationship between the first PSA after sLND and death from PCa. Different definitions of PSA persistence were included in a multivariable model predicting cancer-specific mortality (CSM) after surgery to identify the best cutoff value. We investigated the association between PSA persistence and oncologic outcomes using multivariable regression models. Moreover, the effect of early androgen deprivation therapy (ADT) after sLND was tested according to PSA persistence status and estimated risk of CSM. Results and limitationsWe found an inverse relationship between the first PSA after sLND and the probability of cancer-specific survival. PSA persistence defined as first postoperative PSA ≥0.3 ng/ml provided the best discrimination accuracy (C index 0.757). According to this cutoff, 331 patients (57%) experienced PSA persistence. The median follow-up for survivors was 48 mo (interquartile range 27–74). After adjusting for confounders, men with persistently elevated PSA had higher risk of clinical recurrence (hazard ratio [HR] 1.61), overall mortality (HR 2.20), and CSM (HR 2.59; all p < 0.001) after sLND. Early ADT administration after sLND improved survival only for patients with PSA persistence after surgery (HR 0.49; p = 0.024). Similarly, when PSA persistence status was included in multivariable models accounting for pathologic features, early ADT use after sLND was beneficial only for patients with a predicted risk of CSM at 5 yr of >10%. ConclusionsPSA persistence after sLND independently predicts adverse prognosis, with the best discrimination accuracy for CSM provided by a definition of PSA ≥ 0.3 ng/ml. We showed that when stratifying patients by final pathology results and PSA persistence status, early ADT use after sLND was beneficial only for patients with PSA persistence or with a calculated 5-yr risk of CSM of >10%, which could be useful as we await results from ongoing prospective trials. Patient summaryWe found that for patients with prostate cancer who had lymph nodes removed after their cancer recurred, persistently elevated prostate-specific antigen (PSA) levels predict poorer prognosis. We showed that a PSA level of ≥0.3 ng/ml provides the best accuracy in identifying patients with worse prognosis. This may help to improve risk stratification after lymph node removal and allow physicians to optimize treatment strategies after surgery.

Abstract 1650: Non-invasive imaging tool to predict BRCA2 silencing in the context of prostate cancer

Abstract Background: We recently demonstrated that biallelic as well as monoallelic loss of the DNA damage response (DDR) gene BRCA2 in prostate cancer (PC) cell lines and mCRPC organoids leads to an aggressive form of PC and early androgen deprivation therapy (ADT) resistance (Chakraborty et al.). Clinical studies have established that DDR deficiency is generally associated with a poor prognosis. Very recently, immunohistochemical analysis of mCRPC patient samples by Paschalis et al. revealed that defects in DDR genes (in particular BRCA2 and ATM) are associated with increased prostate-specific membrane antigen (PSMA; folate hydrolase, FOLH1) expression on the cell membrane. PSMA expression can be measured non-invasively in pre-clinical models and human subjects using one of the several positron emission tomography (PET) imaging agents such as [68Ga]-PSMA11 or [124I]-MSK-PSMA11 that are being evaluated in pre-clinical and/or clinical setting. Therefore, we hypothesized that upregulation of PSMA expression can be a marker for BRCA2 loss and this increased expression can be quantified using PET agents both in vitro and in vivo. Experimental design: We investigated the effect of BRCA2 deletion on PSMA expression in the castration sensitive human PC cell line LNCaP at the transcriptional and translational level and quantified the changes using saturation binding assays with [124I]-MSK-PSMA11. Using CRISPR-Cas9 and RNAi-based methods, we silenced BRCA2 in the castration sensitive cell line LNCaP and evaluated its effect on PSMA at the transcriptional and translational level. We carried out saturation binding assay using [124I]-MSK-PSMA11 to measure changes in cell surface PSMA receptor density. Results: BRCA2 knockout was achieved successfully using CRISPR-Cas9 based methods. Immunoblotting analysis revealed that BRCA2 loss resulted in a significant increase in PSMA levels when compared to control LNCaP cell line. Immunohistochemical analysis confirmed this obervation. Cell binding assays demonstrated that BRCA2 null LNCaP cell lines have about 5-6 fold higher uptake of the PET tracer [124I]-MSK-PSMA11. We will be conducting in vivo studies to demonstrate that BRCA2 deletion leads to a significant increase in PSMA signal in mice xenograft models. Conclusions: Our results indicate that BRCA2 silencing leads to significant upregulation of PSMA expression in PC cell lines, which can be imaged using a PSMA targeted PET tracer. These studies were partly supported by DOD-PCRP-Grant # W81XWH-19-1-0536 and PCF Young Investigator Award to Goutam Chakraborty.

Abstract 4761: Lipidomic analysis of circulating lipids across the natural history of prostate cancer identifies aberrant ceramide metabolism

Abstract Background: Obesity is a well established risk factor not only for increased prostate cancer incidence, but for poorer survival from prostate cancer. However, there is limited knowledge on the role of the circulating lipidome in prostate cancer. In order to target lipid metabolism optimally, it is critical to understand the spectrum of changes in circulating lipid profiles and the association with clinical outcome across the natural history of prostate cancer. Aim: To assess the relationship between the plasma lipidome and clinical outcome in localized and metastatic prostate cancer. Methods: Liquid chromatography-tandem mass spectrometry was used to quantitate over 500 lipid species in plasma samples from 3 cohorts (1) 389 men with localized prostate cancer, (2) 44 men with metastatic hormone-sensitive prostate cancer (mHSPC), and (3) 137 men with metastatic castration-resistant prostate cancer (CRPC). Associations between circulating lipids with metastatic relapse, androgen-deprivation therapy (ADT) failure or overall survival for each relevant disease stage were examined by latent class analysis and cox regression. Results: Circulating lipid profiles displaying elevated levels of ceramides were associated with metastatic relapse in localized prostate cancer (HR 5.8, 95% CI 3.0-11, P 1 × 10−6), early ADT failure in mHSPC (HR 2.4, 95% CI 1.1-5.3, P 0.03), and shorter overall survival in CRPC (HR 2.5, 95% CI 1.7-3.7, P 2 × 10−6). ADT failure in mHSPC and shorter overall survival in CRPC were also associated with elevated levels of other sphingolipids (sphingomyelins, hexosylceramides). The prognostic significance of the high risk lipid profiles in localized prostate cancer was independent of clinicopathological characteristics (lipid profile HR 4.7, 95%CI 2.4-9.3, P 7 × 10−6) when modeled with Gleason score (P&amp;lt;0.0001) and pathological stage (P&amp;lt;0.0001). Furthermore, the circulating lipid profiles were independent of metabolic factors (localized prostate cancer lipid profile HR 8.2, 95% CI 2.6-25, P 0.0003 when modeled with diabetes, statin, hypertension, body mass index [BMI]; CRPC lipid profile HR 2.6, 95% CI 1.7-3.8, P x10−6 when modeled with BMI). Conclusion: Elevated circulating ceramides are associated with poorer clinical outcomes across the natural history of prostate cancer (from localized to metastatic hormone-sensitive to metastatic castration resistant prostate cancer). This demonstrates that aberrant lipid metabolism in the patients occurs early in prostate cancer and could be therapeutically targeted in prospective clinical trials to improve prostate cancer outcomes. Citation Format: Lisa Glen Horvath, Hui-Ming Lin, Blossom Mak, Kate Mahon, Nicole Yeung, Maria Docanto, Peter Sutherland, andrew Shepherd, Winston Tan, Arun Azad, Manish Kohli, Peter Meikle, Lisa Butler. Lipidomic analysis of circulating lipids across the natural history of prostate cancer identifies aberrant ceramide metabolism [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4761.

Subsequent risk of acute urinary retention and androgen deprivation therapy in patients with prostate cancer: A population-based retrospective cohort study.

Acute urinary retention (AUR) is associated with hormone imbalance in men. However, limited studies focused on exploring the complications of AUR in patients with prostate cancer (PC) who receive androgen deprivation therapy (ADT). Therefore, we aim to evaluate the subsequent risk of AUR in ADT-treated PC patients. We collected data from 24,464 male patients who were newly diagnosed with prostate malignancy from a longitudinal health insurance database of catastrophic illness in 2000 to 2008. All PC patients were categorized into 2 cohorts, namely, ADT cohort and non-ADT cohort, based on whether or not the patient receives ADT. The patients were followed up until the occurrence of AUR. Multivariate Cox proportional hazard regression and Kaplan–Meier analysis were performed. After a 12-year follow-up, the incidence rates of AUR were 12.49 and 9.86 per 1000 person-years in ADT and non-ADT cohorts, respectively. Compared with the non-ADT cohort, the ADT cohort had a 1.21-fold increase in AUR risk based on the adjusted model (95% CI = 1.03–1.43). In addition, PC patients receiving early ADT treatment within 6 months or receiving only luteinizing hormone-releasing hormone treatment also had significantly increased risk of AUR. ADT was positively associated with AUR risk. PC patients receiving ADT should be informed about the risks of bladder outlet obstruction and AUR, and they may benefit from screening for related risk factors. New guidelines and treatments should be proposed in the future to manage ADT-related lower urinary tract symptoms and reduce the risk of AUR.

Optimal PSA Threshold for Androgen-Deprivation Therapy in Patients with Prostate Cancer following Radical Prostatectomy and Adjuvant Radiation Therapy.

PurposeThe benefits of early administration of androgen-deprivation therapy (ADT) in patients with prostate-specific antigen (PSA)-only recurrent prostate cancer (PCa) following radical prostatectomy (RP) are controversial. We investigated the impact of early versus delayed ADT on survival outcomes in patients with non-metastatic, localized or locally advanced PCa who received radiation therapy (RT) following RP and later developed distant metastasis.Materials and MethodsA retrospective analysis was performed on 69 patients with non-metastatic, localized or locally advanced PCa who received RT following RP and later developed distant metastasis between January 2006 and December 2012. Patients were stratified according to the level of PSA at which ADT was administered (<2 ng/mL vs. ≥2 ng/mL). Study endpoints were progression to castration-resistant prostate cancer (CRPC)-free survival and cancer-specific survival (CSS).ResultsPatients were stratified according to the criteria of 2 ng/mL of PSA at which ADT was administered, based on the Youden sensitivity analysis. Delayed ADT at PSA ≥2 ng/mL was an independent prognosticator of cancer-specific mortality (p=0.047), and a marginally significant prognosticator of progression to CRPC (p=0.051). During the median follow-up of 81.0 (interquartile range 54.2–115.7) months, patients who received early ADT at PSA <2 ng/mL had significantly higher CSS rates compared to patients who received delayed ADT at PSA ≥2 ng/mL (p=0.002). Progression to CRPC-free survival was comparable between the two groups (p=0.331).ConclusionEarly ADT at the PSA level of less than 2 ng/mL confers CSS benefits in patients with localized or locally advanced PCa who were previously treated with RP.

Outcomes of men with recurrent M0 prostate cancer who defer androgen deprivation therapy until metastasis.

5016 Background: Optimal timing and criteria for implementation of androgen deprivation therapy (ADT) in men with relapsed M0 prostate cancer (PCa) remains undefined. Early ADT induces the non-metastatic castration resistant PCa (nmCRPC) clinical state. FDA approved apalutamide (SPARTAN) and enzalutamide (PROSPER) for nmCRPC based on prolongation of metastasis free survival (MFS) which is now considered a valid endpoint for drug approval. Because overall survival (OS) in PCa is usually long and long-term ADT is associated with irreversible adverse events and high costs, we sought to evaluate OS and other outcomes of men with relapsed PCa and ADT deferred until metastasis. Methods: Retrospective review of 2,636 men who had radical prostatectomy (RP) between 1981-2017 and developed biochemically recurrent PCa from a single-institution. Patients who received ADT prior to metastasis were excluded. Kaplan-Meier survival estimates of MFS and OS were defined from RP to event or censor. Multivariable Cox proportional hazards regression was used to identify prognostic factors. Results: 1,686 men treated with deferred ADT until metastasis or censored metastasis-free were eligible. Medians: follow up 10 years (IQR5-16), age 60 years, PSADT 33 months, Gleason &lt; 7 (24%), Gleason 7 (55%), Gleason &gt; 7 (21%). 688 (41%) received salvage radiotherapy. Median MFS and OS were 21 and 22 years, respectively (Table). In multivariable models, age (HR 1.06, 95% CI 1.04-1.1), Gleason &lt; 8 vs ≥8 (HR 0.4; 0.3-0.5) , RP stage (organ confined vs not 0.6; 0.5-0.8), PSADT (0.995, 0.993-0.997) and salvage RT (0.88; 0.81, 0.96) were associated with OS. Conclusions: Deferred ADT in relapsing M0 patients is associated with long OS measured from time of local treatment, comparable to OS with salvage ADT in contemporary experience. Drug approval trials in nmCRPC should focus on patients at high risk for metastasis and death prior to ADT, and determine standardized criteria for initiation of ADT. Prolongation of MFS in nmCRPC requires further validation and may not necessarily reflect a net OS benefit. [Table: see text]

Serum Proteomics on the Basis of Discovery of Predictive Biomarkers of Response to Androgen Deprivation Therapy in Advanced Prostate Cancer.

We investigated the serum proteome of hormone-sensitive prostate cancer patients to determine candidate biomarkers associated with androgen deprivation therapy (ADT) efficacy. Serum proteomes generated using isobaric mass tags for relative and absolute quantitation were analyzed using reverse-phase liquid chromatography coupled to tandem mass spectrometry. The advanced hormone-sensitive prostate cancer cohorts studied were: (1) untreated "paired" pre-ADT and 4-month post-ADT hormone-sensitive patients (n=15); (2) "early ADT failure" patients (n= 10) in whom ADT treatment failed within a short period of time; and (3) "late ADT failure" patients (n= 10) in whom ADT treatment failed after a prolonged response time. Differential abundance was assessed, and ingenuity pathway analysis (IPA) was used to identify interaction networks in selected candidates from these comparisons. Between "post-ADT" and combined "early" and "late" ADT failure groups 149 differentially detected candidates were observed, and between "early" and "late" ADT failure groups 98 candidates were observed; 47 candidates were common in both comparisons. IPA network enrichment analysis of the 47 candidates identified 3 interaction networks (P< .01) including 17-β-estradiol, nuclear factor kappa-light-chain enhancer of activated B cells complex, and P38 mitogen-activated protein kinases as pathways with potential markers of response to ADT. A global proteomic analysis identified pathways with markers of ADT response, which will need validation in independent data sets.

Timing of androgen deprivation monotherapy and combined treatments in castration-sensitive and castration-resistant prostate cancer: a narrative review.

Standard androgen deprivation therapy (ADT) can be initiated early at the time of diagnosis in asymptomatic castration-sensitive advanced prostate cancer. This definition has recently been expanded to also include an early combined treatment with standard ADT and new antihormonal drugs. We aimed to present the best available evidence for the timing of initiation of ADT monotherapy and combined treatments in castration-sensitive/-resistant prostate cancer. For this narrative review, we searched Cochrane reviews in the Cochrane Library, systematic reviews and randomized controlled trials in MEDLINE, phase III and ongoing trials in ClinicalTrials.gov and screened the reference lists to extract articles of interest. One author screened the references which were finally included after assessing their relevance through discussion with other experts in the field. The identified references were grouped by medication (standard ADT, androgen biosynthesis inhibitor, androgen receptor antagonists or combined therapies) and tumor stage (castration sensitive or resistant). The evidence was narratively summarized and discussed in the context of the current therapeutic landscape. Early standard ADT can reduce symptoms of disease progression and may extend progression-free and overall survival. The patient should be well informed about the higher rates of treatment-related side effects. Deferring standard ADT might be indicated only for well-informed or unfit patients. Early standard ADT is increasingly combined with new antihormonal drugs in castration-sensitive metastatic prostate cancer to gain additional survival and quality of life benefits. Combined treatment at the time of development of castration-resistant disease is well established.

LBA18 IMPACT OF TRANSIENT ANDROGEN DEPRIVATION THERAPY (ADT) WITH LEUPRORELIN LP 11.25 MG ON THE HISTOLOGICAL PROGRESSION OF INDOLENT PROSTATE CANCER (PC)–RESULTS OF A PHASE III TRIAL VERSUS ACTIVE SURVEILLANCE (AS)IMPACT OF TRANSIENT ANDROGEN DEPRIVATION THERAPY (ADT) WITH LEUPRORELIN LP 11.25 MG ON THE HISTOLOGICAL PROGRESSION OF INDOLENT PROSTATE CANCER (PC)–RESULTS OF A PHASE III TRIAL VERSUS ACTIVE SURVEILLANCE (AS)

You have accessJournal of UrologyPlenary: Next Frontier1 Apr 2018LBA18 IMPACT OF TRANSIENT ANDROGEN DEPRIVATION THERAPY (ADT) WITH LEUPRORELIN LP 11.25 MG ON THE HISTOLOGICAL PROGRESSION OF INDOLENT PROSTATE CANCER (PC)–RESULTS OF A PHASE III TRIAL VERSUS ACTIVE SURVEILLANCE (AS)IMPACT OF TRANSIENT ANDROGEN DEPRIVATION THERAPY (ADT) WITH LEUPRORELIN LP 11.25 MG ON THE HISTOLOGICAL PROGRESSION OF INDOLENT PROSTATE CANCER (PC)–RESULTS OF A PHASE III TRIAL VERSUS ACTIVE SURVEILLANCE (AS) Olivier Cussenot, Raphaele Renard Penna, Eva Comperat, Abdel-Rahmène Azzouzi, Pierre Costa, Stéphane Larre, Alain Ruffion, Ludmila Fasla, Dominque Delavierre, Xavier Rebillard, Christian Pfister, Jean-Philippe Fendler, Jorgea Villamizar Vesga, and Frédéric Staerman Olivier CussenotOlivier Cussenot More articles by this author , Raphaele Renard PennaRaphaele Renard Penna More articles by this author , Eva ComperatEva Comperat More articles by this author , Abdel-Rahmène AzzouziAbdel-Rahmène Azzouzi More articles by this author , Pierre CostaPierre Costa More articles by this author , Stéphane LarreStéphane Larre More articles by this author , Alain RuffionAlain Ruffion More articles by this author , Ludmila FaslaLudmila Fasla More articles by this author , Dominque DelavierreDominque Delavierre More articles by this author , Xavier RebillardXavier Rebillard More articles by this author , Christian PfisterChristian Pfister More articles by this author , Jean-Philippe FendlerJean-Philippe Fendler More articles by this author , Jorgea Villamizar VesgaJorgea Villamizar Vesga More articles by this author , and Frédéric StaermanFrédéric Staerman More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.03.089AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Indolent forms of PC or low-risk prostate cancer (LRPC) represent 50% of newly diagnosed PC. Definition of LRPC and AS candidates remains problematic due to the lack of relevant markers of PC aggressiveness and difficulties in assessing disease progression under AS. Current knowledge suggests that PC aggressiveness could be assessed by response to early ADT. Long-term administration of a 5-alpha-reductase inhibitor may prevent the development of PC and reverse LRPC. Preliminary results of a pilot series at 2 French urology centers in LRPC pts receiving 2 drugs (analogs and 5-alpha-reductase inhibitor) for 3 months (mo), show tumor regression in about 60% of cases and suggest that LRPC can be reversed by ADT. Our study aims at confirming these results on a larger scale. METHODS This was an open randomized phase III study comparing 2 treatment strategies. Arm A = AS after a single subcutaneous injection of Leuprorelin LP 11.25mg. Arm B = usual AS. Pts were eligible if they had a T1c or T2a PC, PSA inferior or equal to 10 ng/ml, Gleason score (GS) inferior or equal to 6 & staging Bx with 12 or more cores revealing the presence of positive cores & absence of core with tumor length > 3mm. The main endpoint was negative Bx at 12 mo. Pts were stratified according to age at diagnosis, PSA (total, density & nadir), testosterone, dynamic MRI staging, % of positive cores and length of tumor on the diagnosis biopsy. Secondary objectives were number of pts with GS equal or superior than 7, progression over time of disease clinical symptoms (IPSS score), tumor radiological progression by dynamic MRI, PSA progression, HAD Scale (anxiety) and International Index of Erectile Function (IIEF-5). RESULTS 115 eligible men from 22 sites were randomized in arm A (58 pts) & arm B (57 pts). The number of negative biopsies at 12 mo was statistically different (p=0.03) between arm A (28 (53%)) & arm B (17 (32%)). Among the secondary endpoints, the arm A strategy statistically improved outcome on: IPSS at 9 mo, PSA reduction at 3, 6 & 9 mo. Moreover, at 12 mo IIEF-5 score was not statistically different between the 2 arms. Other endpoints points were not significantly improved. No serious adverse events related to the study drug were observed. CONCLUSIONS Results obtained with 3mo of Leuprorelin for LRPC suggest that ADT can be used to reverse LRPC lesions, hence improving the results obtained with subsequent AS. Early ADT led to a better quality of life at 9 months. This strategy also allows detecting hidden aggressive disease. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e1076-e1077 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Olivier Cussenot More articles by this author Raphaele Renard Penna More articles by this author Eva Comperat More articles by this author Abdel-Rahmène Azzouzi More articles by this author Pierre Costa More articles by this author Stéphane Larre More articles by this author Alain Ruffion More articles by this author Ludmila Fasla More articles by this author Dominque Delavierre More articles by this author Xavier Rebillard More articles by this author Christian Pfister More articles by this author Jean-Philippe Fendler More articles by this author Jorgea Villamizar Vesga More articles by this author Frédéric Staerman More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Metabolic changes in patients with prostate cancer during androgen deprivation therapy.

Androgen deprivation therapy continues to be widely used for the treatment of prostate cancer despite the appearance of new-generation androgen-receptor targeting drugs after 2000. Androgen deprivation therapy can alleviate symptoms in patients with metastatic prostate cancer and might have a survival benefit in some patients, but it causes undesirable changes in lipid, glucose, muscle or bone metabolism. These metabolic changes could lead to new onset or worsening of diseases, such as obesity, metabolic syndrome, diabetes mellitus, cardiovascular disease, sarcopenia or fracture. Several studies examining the influence of androgen deprivation therapy in Japanese patients with prostate cancer also showed that metabolic changes, such as weight gain, dyslipidemia or fat accumulation, can occur as in patients in Western countries. Efforts to decrease these unfavorable changes and events are important. First, overuse of androgen deprivation therapy for localized or elderly prostate cancer patients should be reconsidered. Second, intermittent androgen deprivation therapy might be beneficial for selected patients who suffer from impaired quality of life as a result of continuous androgen deprivation therapy. Third, education and instruction, such as diet or exercise, to decrease metabolic changes before initiating androgen deprivation therapy is important, because metabolic changes are likely to occur in the early androgen deprivation therapy period. Fourth, routine monitoring of weight, laboratory data or bone mineral density during androgen deprivation therapy are required to avoid unfavorable events.

External beam radiation for the treatment of castration-resistant prostate cancer following primary hormonal therapy with androgen ablation: Analysis and outcome of 21 patients

Patients who undergo early androgen-deprivation therapy for prostate cancer may eventually develop castration-resistant prostate cancer. However, no optimal treatment for non-metastasized castration-resistant prostate cancer has yet been established. In the present retrospective, single-institutional study, the radiotherapy (RT) outcomes were evaluated in patients who underwent androgen-deprivation therapy for non-metastatic prostate cancer and subsequently developed castration-resistant disease. Following a thorough chart review, the data of 21 patients with castration-resistant prostate cancer who were treated between 2000 and 2010 with external beam radiation therapy (EBRT) at a prostate radiation dose of >45 Gy were evaluated. Of the 21 patients, 16 (76%) developed biochemical recurrence after RT, with a mean time to biochemical recurrence of 17 months. A total of 18 patients succumbed to the disease during follow-up, with a mean survival of 3 years after RT. A radiation dose of >66 Gy was associated with a longer time to biochemical recurrence after RT (P=0.011) and a longer survival, compared with a dose of ≤66 Gy (P=0.028). The mean overall survival time after RT was 42 months and did not depend on the primary hormonal treatment. Prostate-specific survival time was negatively associated with the Gleason score at diagnosis. The prostate-specific antigen (PSA) concentration prior to RT was a prognostic factor for biochemical recurrence of prostate cancer after RT, as well as for prostate cancer-specific survival. Finally, the multivariate analysis revealed that age, PSA concentration prior to RT and a high Gleason score were independent prognostic factors for prostate cancer-specific survival. Overall, our study findings demonstrated that disease progression was common after EBRT for castration-resistant prostate cancer and that survival was limited. However, young patients and those with low-risk disease at the time of diagnosis may benefit from RT.

Association between ischaemic bowel syndromes and androgen deprivation therapy in patients with prostate cancer: a retrospective cohort study

ObjectiveThis study investigated the risk of ischaemic bowel syndrome (IBS) in androgen deprivation therapy (ADT) users to explore the long-term outcomes of patients with prostate cancer (PC) receiving ADT treatment.MethodsWe...

Influence of 1 year of androgen deprivation therapy on lipid and glucose metabolism and fat accumulation in Japanese patients with prostate cancer.

We prospectively examined influence of androgen deprivation therapy (ADT) on lipid and glucose metabolisms in Japanese patients with prostate cancer. Patients with prostate cancer who were hormone-naive and scheduled to receive long-term ADT were recruited between 2011 and 2013. Body weight, abdominal circumference and blood testing associated with lipid and glucose metabolism were recorded every 3 months during 1 year of ADT. Computed tomography (CT) was performed to measure areas of subcutaneous and visceral fat before and after 1 year of ADT. ADT was limited to a luteinizing hormone-releasing hormone (LHRH) agonist with or without bicalutamide. Of 218 patients registered, data were available from 177 patients who completed 1 year of ADT. Of these, CT was performed before and after 1 year of ADT in 88 patients. Median age was 75 years (range, 49-85 years). Median PSA before ADT was 16.7 ng ml(-1) (range, 0.3-3316). Clinical stage was B (54.2%), C (23.2%) and D (20.9%). Mean increases in body weight and abdominal circumference after 1 year of ADT were 2.9 and 3.0%, respectively. Mean increases in total, low-density lipoprotein and high-density lipoprotein cholesterol and triglycerides were 10.6, 14.3, 7.8 and 16.2%, respectively. Mean increases in fasting blood sugar and hemoglobin A1c (HbA1c) were 3.9 and 2.7%, respectively. Lipid alterations were noted in patients without comorbidities, whereas changes in HbA1c were noted in patients with diabetes mellitus at baseline. These lipid and glucose alterations were prominent in the early ADT period. Both visceral and subcutaneous fat, as measured by CT, increased by >20%. The increase in subcutaneous fat was significantly greater than that in visceral fat (P=0.028). One year of ADT significantly changed lipid and glucose metabolism in Japanese patients with prostate cancer. Patient characteristics or comorbidities at baseline may be associated with ADT-induced metabolic changes.

High PSA anxiety and low health literacy skills: drivers of early use of salvage ADT among men with biochemically recurrent prostate cancer after radiotherapy?

Although commonly used, early initiation of salvage androgen deprivation therapy (ADT) has not been proven to enhance survival. We evaluated whether prostate-specific antigen (PSA) anxiety or health literacy are associated with use of early salvage ADT among men with recurrent prostate cancer after radiotherapy. The prospective Comprehensive, Observational, Multicenter, Prostate Adenocarcinoma Registry was used to study 375 men with biochemically recurrent prostate cancer after external beam radiation or brachytherapy. Multivariable logistic regression was used to determine whether PSA anxiety and health literacy are associated with salvage ADT as initial management after biochemical recurrence. Sixty-eight men (18.1%) received salvage ADT as initial management for PSA recurrence. Men with high PSA anxiety were twice as likely to receive salvage ADT compared with men who did not have high PSA anxiety on both univariable [28.8% versus 13.1%; odds ratio (OR) 2.15; 95% confidence interval (CI) 1.16-4.00; P = 0.015] and multivariable analysis [adjusted OR (AOR) 2.36; 95% CI 1.21-4.62; P = 0.012]. Furthermore, men who had higher levels of health literacy were nearly half as likely to undergo salvage ADT compared with men who had lower levels of health literacy on univariable analysis (15.2% versus 26.3%; OR 0.50; 95% CI 0.29-0.88; P = 0.016), with a trend toward this association on multivariable analysis (AOR 0.58; 95% CI 0.32-1.05; P = 0.07). Among men with PSA recurrence after radiotherapy, odds of use of salvage ADT were nearly twice as great among men with high PSA anxiety or low health literacy, suggesting that these men are receiving higher rates of unproven treatment. Given that early salvage ADT is costly, worsens quality of life, and has not been shown to improve survival, quality improvement strategies are needed for these individuals.

MP82-15 DOES EARLY ANDROGEN DEPRIVATION THERAPY AFTER BIOCHEMICAL RECURRENCE FOLLOWING RADICAL PROSTATECTOMY INCREASE OVERALL SURVIVAL? RESULTS FROM SEARCH

INTRODUCTION AND OBJECTIVES: Androgen deprivation therapy (ADT) isstandard therapy formenwithmetastaticdisease (mets)e whether they present with mets or mets develop after failed curative treatment. In the PSA era, a rising PSA is the first sign of recurrence after treatment andADT ismost often today begunprior tomets.Whether earlier initiation of ADT has a survival benefit remains hotly debated. We examined the relationship between early ADT and overall survival in men who had a biochemical recurrence (BCR) after radical prostatectomy (RP). METHODS: We retrospectively analyzed data on 1,053 patients from 6 VA hospitals in the SEARCH database who had a BCR after RP between 1988 and 2013. Early ADT was defined as receiving ADT when PSA 5 ng/mL. Thus, the reference group contained patients who never received ADT or received late ADT (PSA >5 ng/mL). Cox models were used to test the association between early ADT and time from BCR to overall survival.Modelswereadjusted for age, race, surgical center, yearof surgery,PSA,pathologicalGleasonscore, time fromsurgery to recurrence, pathological features, and radiation therapy. In sensitivity analyses, we redefined early ADT as pre-ADT PSA 10 ng/mL or 20 ng/mL and also compared results for patients who did not receive ADT until time of mets. RESULTS: Median follow-up after recurrence was 4.8 years. 219 patients (21%) hadearlyADTand834did not.Onunivariable analysis, early ADTwas associatedwith decreased risk of death (HR0.74, p1⁄40.010). After adjusting for imbalances between the two groups, early ADT remained associated with decreased risk of death (HR 0.72, p1⁄40.021). When early ADTwas redefined as pre-ADT PSA 10 ng/mL, this association remained on multivariable analysis (HR 0.79, p1⁄40.045). However, when early ADT was defined as pre-ADT PSA 20 ng/mL, the association between early ADTandoverall survival was no longer significant (HR0.83, p1⁄40.107). ADT did not show a statistically significant survival benefit among those who received ADT at time of mets (HR 0.74, p1⁄40.152). CONCLUSIONS: We found an overall survival benefit for men with BCR after RP if ADT was initiated before PSA reaches 10 ng/mL, and this benefit was stronger when ADT was initiated before PSA reaches 5 ng/mL. While the survival benefits of ADT must be weighed against long-term side effects, our data support treating with ADT before the time of mets in order to increase overall survival. Further studies are warranted to support these findings.