Years Of Androgen Deprivation Therapy Research Articles

CD44 and CD133 protein expression might serve as a prognostic factor for early occurrence castration-resistant prostate cancer.

The occurrence of castration-resistant prostate cancer (CRPC) varies in patients with advanced prostate cancer (PCa) undergoing androgen deprivation therapy (ADT). The rate of occurrence of CRPC may be related to the presence of prostate cancer stem cells (CSC). Thus, this study aims to evaluate the presence of CSC markers (CD44 and CD133) in histopathology tissue at the time of diagnosis and their correlation with the occurrence of CRPC in patients with advanced PCa within 2 years of ADT. A retrospective case-control study was conducted to evaluate the incidence of CRPC within 2 years. The inclusion criteria were patients with PCa who had received treatment with ADT and a first-generation anti-androgen (AA) for 2 years. We classified patients based on whether they developed CRPC within 2 years (CRPC) of the therapy or did not experience CRPC within 2 years (non-CRPC) of the therapy. We performed immunohistochemical (IHC) staining for CD44 and CD133 on the prostate biopsy tissue samples. Data were collected from records spanning 2011-2019. We analyzed a total of 65 samples, including 22 patients with CRPC and 43 patients with non-CRPC who had received treatment with LHRH agonists and AA for up to 2 years. Our findings showed a significant H-score difference in CD44 protein expression between CRPC prostate adenocarcinoma samples 869 (200-1329) and non-CRPC 524 (154-1166) (p = 0.033). There was no significant difference in CD133 protein expression between the two groups (p = 0.554). However, there was a significant difference in the nonoccurrence of CRPC between the high expressions of both CD44 and CD133 groups with other expressions of CD44/CD133 groups (25% vs. 75%; p = 0.011; odds ratio = 4.29; 95% confidence interval [1.34, 13.76]). This study found a low expression of at least one CD44/CD133 protein in the patients without early occurrence of CRPC. This result might suggest that CD44/CD133 may function as a potential prognostic marker for PCa, especially in a low expression, to identify patients who have a better prognosis regarding the occurrence of early CRPC.

Long-term results of dose escalation (80 vs 70 Gy) combined with long-term androgen deprivation in high-risk prostate cancers: GETUG-AFU 18 randomized trial.

LBA259 Background: Radiotherapy (RT) delivered in combination with androgen deprivation therapy (ADT) improve survival for patients with prostate adenocarcinoma. RT given at a dose of 80 Gy is generally well tolerated but the occurrence of grade 3-4 toxicities is significantly more frequent than at a dose of 70 Gy. Furthermore, ADT has been reported to increase RT-related toxicity. Thus, we aimed to evaluate the efficacy and safety of dose escalation in combination with long term ADT in high-risk prostate cancer patients. Methods: The GETUG-AFU 18 study, sponsored by Unicancer, is a phase III randomized trial. Eligible patient had high-risk (cT3-T4 or PSA≥ 20 ng/ml or Gleason score ≥ 8-10) prostate adenocarcinoma with negative lymph-nodes status on CT-scan or MRI. Patients were randomly assigned to dose-escalated RT (80 Gy) or conventional-dose (70 Gy) with 3 years of ADT in both arms. Randomization (1:1) was stratified on pelvic lymph-nodes dissection (PLND; yes or no) and institution. Pelvic nodal irradiation (46 Gy) was performed for all patients except in case of negative PLND. The primary endpoint is the biochemical or clinical progression-free survival (bcPFS) at 5 years following ASTRO-Phoenix definition. Secondary endpoints are overall survival (OS), acute and late toxicity (CTCAE v3), and quality of life. To improve bcPFS from 65 to 75% (Hazard Ratios [HR] = 0.67), 500 patients were required (a= 5% and 1-b= 80%) with 197 events at 5 years. Results: 505 patients were included between June 2009 and January 2013. Main characteristics of the population were median age of 70.6 years (range 52-80); 268 (53.1%) patients with a Gleason score ≥ 8; median PSA value of 13.8 ng/ml (0.4-109.9); 62.3% of patient with cT3, and 16.4% with PLND. There was no imbalance between groups for major prognostic factors. The bcPFS was significantly improved in the dose-escalated RT arm compared with conventional RT arm (HR = 0.56, [95% CI, 0.40-0.76], p = 0.0005). The 5-year bcPFS was 91.4% (95% CI, 87.0-94.4) and 88.1% (95% CI, 83.2-91.6), and the 7-year bcPFS 88.1% (95% CI, 83.1-91.7) and 79.2% (95% CI, 73.1-84.0) in dose-escalated RT and conventional RT, respectively. We did observe significant differences in prostate cancer-specific survival (HR = 0.48 [95% CI, 0.27-0.83], p = 0.0090) and overall survival (HR = 0.61 [95% CI, 0.44-0.85], p = 0.0039). No prognostic factors were identified for bcPFS. Regarding late toxicities, there was no significant difference between arms with 78.2% and 76.1% of ≥Grade 2 toxicity with dose-escalated RT and conventional RT, respectively. Conclusions: Dose-escalation RT in combination with long-term ADT is effective and safe, increasing not only the bcPFS rate but also specific survival and overall survival in high-risk prostate cancer patients without increasing long-term toxicity. Clinical trial information: NCT00967863 .

Secondary Cancer after Androgen Deprivation Therapy in Prostate Cancer: A Nationwide Study.

Androgen signaling is associated with various secondary cancer, which could be promising for potential treatment using androgen deprivation therapy (ADT). This study investigated whether ADT use was associated with secondary cancers other than prostate cancer in a nationwide population-based cohort. A total, 278,434 men with newly diagnosed prostate cancer between January 1, 2002 and December 31, 2017 were identified. After applying the exclusion criteria, 170,416 men were enrolled. The study cohort was divided into ADT and non-ADT groups by individual matching followed by propensity score matching (PSM). Study outcomes were incidence of all male cancers. Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of events. During a median follow-up of 4.5 years, a total of 11,059 deaths (6,329 in the ADT group and 4,730 in the non-ADT group) after PSM were found. After PSM, the overall all-cause of secondary cancer incidence risk of the ADT group was higher than that of the non-ADT group (HR: 1.312, 95% CI: 1.23-1.36; adjusted HR: 1.344, 95% CI: 1.29-1.40). The ADT group showed higher risk of overall brain and other central nervous system (CNS) cancer-specific incidence than the non-ADT group (adjusted HR: 1.648, 95% CI: 1.21-2.24). The ADT group showed lower risks of overall cancer-specific incidence for stomach, colon/rectum, liver/inflammatory bowel disease (IBD), gall bladder/extrahepatic bile duct, lung, bladder, and kidney cancers than the non-ADT group. When the duration of ADT was more than 2 years of ADT, the ADT group showed higher risk of cancer-specific incidence for brain and other CNS cancers but lower risk of cancer-specific incidence for liver/IBD and lung cancers than the non-ADT group. This study demonstrates that ADT could affect cancer-specific incidence for various cancers.

The heterogeneity and clonal evolution analysis of the advanced prostate cancer with castration resistance

BackgroundNowadays, the incidence rate of advanced and metastatic prostate cancer at the first time of diagnosis grows higher in China yearly. At present, androgen deprivation therapy (ADT) is the primary treatment of advanced prostate cancer. However, after several years of ADT, most patients will ultimately progress to castration-resistant prostate cancer (CRPC). Previous studies mainly focus on Caucasian and very few on East Asian patients.MethodsIn this study, the pre- and post-ADT tumor samples were collected from five Chinese patients with advanced prostate cancer. The whole-exome sequencing, tumor heterogeneity, and clonal evolution pattern were analyzed.ResultsThe results showed that the gene mutation pattern and heterogeneity changed significantly after androgen deprivation therapy. Tumor Mutational Burden (TMB) and Copy Number Alteration (CNA) were substantially reduced in the post-treatment group, but the Mutant-allele tumor heterogeneity (MATH), Socio-Demographic Index (SDI), Intratumor heterogeneity (ITH), and weighted Genome Instability Index (wGII) had no significant difference. According to the clone types and characteristics, the presence of main clones in five pre-and post-treatment samples, the clonal evolution pattern can be further classified into two sub-groups (the Homogeneous origin clonal model or the Heterogeneous origin clonal model). The Progression-free survival (PFS) of the patients with the “Homogeneous origin clonal model” was shorter than the “Heterogeneous origin clonal model”. The longer PFS might relate to MUC7 and MUC5B mutations repaired. ZNF91 mutation might be responsible for resistance to ADT resistance.ConclusionOur findings revealed potential genetic regulators to predict the castration resistance and provide insights into the castration resistance processes in advanced prostate cancer. The crosstalk between clonal evolution patterns and tumor microenvironment may also play a role in castration resistance. A multicenter-research including larger populations with different background are needed to confirm our conclusion in the future.

ESTRO-ACROP recommendations for evidence-based use of androgen deprivation therapy in combination with external-beam radiotherapy in prostate cancer

Background and purposeThere is no consensus concerning the appropriate use of androgen deprivation therapy (ADT) during primary and postoperative external-beam radiotherapy (EBRT) in the management of prostate cancer (PCa). Thus, the European Society for Radiotherapy and Oncology (ESTRO) Advisory Committee for Radiation Oncology Practice (ACROP) guidelines seeks to present current recommendations for the clinical use of ADT in the various indications of EBRT. Material and methodsA literature search was conducted in MEDLINE PubMed that evaluated EBRT and ADT in prostate cancer. The search focused on randomized, Phase II and III trials published in English from January 2000 to May 2022. In case topics were addressed in the absence of Phase II or III trials, recommendations were labelled accordingly based on the limited body of evidence. Localized PCa was classified according to D’Amico et al. classification in low-, intermediate and high risk PCa. The ACROP clinical committee identified 13 European experts who discussed and analyzed the body of evidence concerning the use of ADT with EBRT for prostate cancer. ResultsKey issues were identified and are discussed: It was concluded that no additional ADT is recommended for low-risk prostate cancer patients, whereas for intermediate- and high-risk patients four to six months and two to three years of ADT are recommended. Likewise, patients with locally advanced prostate cancer are recommended to receive ADT for two to three years and when ≥ 2 high-risk factors (cT3-4, ISUP grade ≥ 4 or PSA ≥ 40 ng/ml) or cN1 is present ADT for three years plus additional Abiraterone for two years is recommended. For postoperative patients no ADT is recommended for adjuvant EBRT in pN0 patients whereas for pN1 patients adjuvant EBRT with long-term ADT is performed for at least 24 to 36 months. In the setting of salvage EBRT ADT is performed in biochemically persistent PCa patients with no evidence of metastatic disease. Long-term ADT (24 months) is recommended in pN0 patients with high risk of further progression (PSA ≥ 0.7 ng/ml and ISUP grade group ≥ 4) and a life expectancy of over ten years, whereas short-term ADT (6 months) is recommended in pN0 patients with lower risk profile (PSA < 0.7 ng/ml and ISUP grade group 4). Patients considered for ultra-hypofractionated EBRT as well as patients with image based local recurrence within the prostatic fossa or lymph node recurrence should participate in appropriate clinical trials evaluating the role of additional ADT. ConclusionThese ESTRO-ACROP recommendations are evidence-based and relevant to the use of ADT in combination with EBRT in PCa for the most common clinical settings.

PD22-01 ONCOLOGICAL OUTCOMES OF SENTINEL LYMPH NODE PROCEDURE-GUIDED RADIOTHERAPY VERSUS IMAGING-GUIDED RADIOTHERAPY FOR CLINICALLY LOCALIZED PROSTATE CANCER – A MULTICENTER, RETROSPECTIVE, PROPENSITY SCORE WEIGHTED COMPARISON

You have accessJournal of UrologyCME1 May 2022PD22-01 ONCOLOGICAL OUTCOMES OF SENTINEL LYMPH NODE PROCEDURE-GUIDED RADIOTHERAPY VERSUS IMAGING-GUIDED RADIOTHERAPY FOR CLINICALLY LOCALIZED PROSTATE CANCER – A MULTICENTER, RETROSPECTIVE, PROPENSITY SCORE WEIGHTED COMPARISON Hilda de Barros, Nikolaos Grivas, Jan Duin, Daan Mulder, Vincent van der Noort, Arjen Noordzij, Esther Wit, Eva Schaake, Pim van Leeuwen, and Henk van der Poel Hilda de BarrosHilda de Barros More articles by this author , Nikolaos GrivasNikolaos Grivas More articles by this author , Jan DuinJan Duin More articles by this author , Daan MulderDaan Mulder More articles by this author , Vincent van der NoortVincent van der Noort More articles by this author , Arjen NoordzijArjen Noordzij More articles by this author , Esther WitEsther Wit More articles by this author , Eva SchaakeEva Schaake More articles by this author , Pim van LeeuwenPim van Leeuwen More articles by this author , and Henk van der PoelHenk van der Poel More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002564.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Insufficient sensitivity of current imaging techniques for nodal staging has led to the exploration of the sentinel lymph node biopsy (SLNB) to select primary prostate cancer (PCa) patients that might benefit from whole-pelvic nodal radiotherapy (WPRT). In this study, we aimed to evaluate oncological outcomes of SLNB-based RT compared to imaging-based RT in cN0M0 PCa patients with an increased estimated risk of nodal metastases. METHODS: This multicenter, retrospective cohort study included 522 cN0 primary PCa patients with a Briganti nomogram-estimated nodal risk >5% treated with external beam RT (EBRT) between 2007-2018. Nodal staging was performed either by radiological staging (261 (50%) patients) or by radiological staging and an additional robot-assisted laparoscopic SLNB (261 (50%) patients). All patients received RT to the prostate and 6 months to 3 years of androgen deprivation therapy (ADT), whereas patients with a histologically positive sentinel node (pN1) also received RT to the pelvic LNs with 3 years of ADT. Endpoints included biochemical recurrence-free survival (BCR-FS) and radiological recurrence-free survival (RR-FS). Propensity score weighted (PSW) multivariable Cox regression analysis was performed to determine independent predictors of BCR and RR. RESULTS: Patients staged with SLNB had a higher rate of extracapsular extension (63% vs 35%, P <0.001) and were at higher risk of nodal metastases (43% vs 29%, P=0.002) compared to imaging-only staged patients. Median follow-up after primary treatment was 64 months (IQR 41-95). In total, 111 patients developed a BCR (SLNB=51, non-SLNB=60) and 98 patients developed a radiological recurrence (SLNB=50, non-SLNB=48; Fig 1). In PSW multivariable Cox regression analyses, SLNB-based RT was an independent predictor of both BCR (HR 0.38, 95% CI 0.25-0.59, P <0.001) and RR (HR 0.44, 95% CI 0.28-0.69, P <0.001). CONCLUSIONS: SLNB-guided RT is associated with a decreased risk of BCR and RR when compared to prostate-only RT in cN0 PCa patients. These results suggest an important role for SLNB in selecting cN0 PCa patients that might profit from WPRT and ADT intensification, and justify a prospective comparison. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e402 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hilda de Barros More articles by this author Nikolaos Grivas More articles by this author Jan Duin More articles by this author Daan Mulder More articles by this author Vincent van der Noort More articles by this author Arjen Noordzij More articles by this author Esther Wit More articles by this author Eva Schaake More articles by this author Pim van Leeuwen More articles by this author Henk van der Poel More articles by this author Expand All Advertisement PDF DownloadLoading ...

The impact of androgen deprivation therapy on bone mineral density in men treated for paraphilic disorder: A retrospective cohort study.

Guidelines suggest treating men with paraphilic disorder with androgen-deprivation therapy (ADT). However, little evidence is available about the long-term impact on bone loss and how to manage this adverse event. The aim of this study is to assess the impact of ADT on bone mineral density (BMD) in men treated for paraphilic disorder with the androgen receptor blocker cyproterone acetate (CPA) and/or GnRH agonist triptoreline (GnRHa) and to evaluate the effect of treatment with bisphosphonates. Baseline and follow-up dual-energy X-ray absorptiometry scan (DXA-scan) data (lumbar and femoral T-scores) were retrospectively extracted from electronic medical files of paraphilic men who received CPA and/or GnRHa. A total of 53 patients with a mean age of 39.1 years (range 17.5-74.6) were included. Lumbar (-0.39 ± 0.17, Mean ± SEM, p=0.046), femoral neck (-0.34 ± 0.09, p=0.002) and total femur (-0.33 ± 0.12, p=0.014) T-scores decreased significantly in the CPA-only group (n=13) during a mean follow-up of 6.0 ± 5.3 years. In the GnRHa group (n=29), T-scores at all sites decreased significantly over 6.6 ± 4.4 years (lumbar: -0.55 ± 0.12, p<0.001, femoral neck: -0.53 ± 0.09, total femur: -0.44 ± 0.09, p<0.001). In the group, who received bisphosphonates (n=11), no significant T-score change was observed (lumbar: -0.25 ± 0.14, p=0.106, femoral neck -0.15 ± 0.17, p=0.402, total femur -0.25 ± 0.14, p=0.106) during 5.0 ± 2.8 years of follow-up. Following a mean duration of 6 years of ADT, we observed a significant decline in BMD of approximately half a standard deviation in T-score at lumbar and femoral site. Although the number of patients who received bisphosphonates was limited, this treatment seems to have a positive stabilizing effect on bone density.

Real-world evaluation of upfront docetaxel in metastatic castration-sensitive prostate cancer.

BACKGROUNDThe majority of patients with newly diagnosed metastatic prostate cancer (PC) initially respond to androgen deprivation therapy (ADT) and are classified as metastatic castration-sensitive PC (mCSPC). Following months to years of ADT, the disease tends to become resistant to ADT. Recent randomized phase-III trials demonstrated a survival benefit with the addition of upfront docetaxel to ADT in mCSPC. Following its implementation in routine care, this combined treatment strategy requires more detailed evaluation in a real-world setting.AIMTo assess the real-world outcome and safety of upfront docetaxel treatment in mCSPC.METHODSA multicenter retrospective cohort study in the Southeast Health Care Region of Sweden was performed. This region includes approximately 1.1 million citizens and the oncology departments of Linköping, Jönköping, and Kalmar. All patients given upfront docetaxel for mCSPC from July 2015 until December 2017 were included. The primary endpoint was progression-free survival (PFS) at 12 mo, and the secondary endpoints were PFS at 24 mo, overall survival (OS), treatment intensity, adverse events, and unplanned hospitalizations. Exploratory analyses on potential prognostic parameters were performed.RESULTSNinety-four patients were eligible and formed the study cohort. PFS at 12 and 24 mo was 75% (95%CI: 66–84) and 58% (46–70), respectively. OS at 12 and 24 mo was 93% (87–99) and 86% (76–96). A total of 91% of patients (n = 86) were given docetaxel according to the standard protocol of 75 mg/m2 every 3 wk (6 cycles), while 9% (n = 8) received a modified protocol of 50 mg/m2 every 2 wk (9 cycles). The average overall dose intensity for those commencing standard treatment was 91%. Univariate Cox regression analyses show that baseline PSA > 180 vs < 180 and the presence of distant metastases vs locoregional lymph node metastases were only negative prognostic factors (HR 2.86, 95%CI: 1.39–5.87, P = 0.0041 and 3.36, 95%CI: 1.03–10.96, P = 0.045). Following multivariate analysis, statistical significance remained for PSA (2.51, 95%CI: 1.21–5.19, P = 0.013) but not for metastatic status (2.60, 95%CI: 0.78–8.65, P = 0.12). Febrile neutropenia was recorded in 21% (n = 20) of patients, and 26% (n = 24) had at least one episode of unplanned hospitalization under and up to 30 d after the treatment course.CONCLUSIONResults from this study support the implementation of upfront docetaxel plus ADT as part of the standard of care treatment strategy in mCSPC.

O22 ANDROGEN DEPRIVATION THERAPY AND THE RISK FOR INGUINAL HERNIA

Abstract Aim To investigate whether androgen deprivation therapy (ADT) for prostate cancer increases the risk for inguinal hernia. Material and Methods A population-based nested case-control study based on data from the Prostate Cancer Database Sweden. The cohort included men with prostate cancer who had not received curative treatment. Men who had been diagnosed with inguinal hernia or had undergone inguinal hernia repair (n = 1324) were cases and controls were men, not diagnosed, nor operated on for inguinal hernia, matched on birth year (n = 13 240). Conditional multivariate logistic regression models were used to assess any temporal association between ADT and inguinal hernia, adjusting for confounders. Results Odds Ratio [OR] for repair of inguinal hernia 0-1 years from start of ADT was 0.5 (95% confidence Interval (CI)) 0.38-0.68), between 1 and 3 years after, the OR was 0.35 (95% CI 0.26-0.47), 3-5 years after, the OR was 0.39 (95% CI 0.26-0.56), 5-7 years after, the OR was 0.6, (95% CI: 0.41-0.97), and &amp;gt; 9 years after, the OR was 3.68 (95% CI 2.45-5.53). Conclusions The marked increase in OR for inguinal hernia after 9 years of ADT supports the hypothesis that low testosterone levels increase the risk for inguinal hernia. The low risk for inguinal hernia during the first eight years on ADT is likely caused by selection of men with advanced cancer unlikely to be diagnosed or treated for inguinal hernia. This finding may support the hypothesis that sex hormones plays a crucial role in inguinal hernia development.

Androgen Deprivation Therapy and the Risk for Inguinal Hernia: An Observational Nested Case Control Study

It has been suggested that hypogonadism increases the risk for inguinal hernia (IH). The aim of this study was to investigate any association between androgen deprivation therapy (ADT) for prostate cancer and increased risk for IH. The study population in this population-based nested case-control study was based on data from the Prostate Cancer Database Sweden. The cohort included all men with prostate cancer who had not received curative treatment. Men who had been diagnosed or had undergone IH repair (n = 1,324) were cases and controls, where not diagnosed, nor operated on for IH, matched only on birth year (n = 13,240). Conditional multivariate logistic regression models were used to assess any temporal association between ADT and IH, adjusting for marital status, education level, prostate cancer risk category, Charlson Comorbidity Index, ADT, time since prostate cancer diagnosis, and primary prostate cancer treatment. Odds ratio (OR) for diagnosis/repair of IH 0 to 1 year from start of ADT was 0.5 (95% confidence interval [CI] = [0.38, 0.68]); between 1 and 3 years after, the OR was 0.35 (95% CI = [0.26, 0.47]); between 3 and 5 years after, the OR was 0.39 (95% CI = [0.26, 0.56]); between 5 and 7 years after, the OR was 0.6 (95% CI = [0.41, 0.97]); and >9 years after, the OR was 3.68 (95% CI = [2.45, 5.53]). The marked increase in OR for IH after 9 years of ADT supports the hypothesis that low testosterone levels increase the risk for IH. The low risk for IH during the first 8 years on ADT is likely caused by selection of men with advanced cancer unlikely to be diagnosed or treated for IH.

Comparison of Multimodal Therapies and Outcomes Among Patients With High-Risk Prostate Cancer With Adverse Clinicopathologic Features

The optimal management strategy for high-risk prostate cancer and additional adverse clinicopathologic features remains unknown. To compare clinical outcomes among patients with high-risk prostate cancer after definitive treatment. This retrospective cohort study included patients with high-risk prostate cancer (as defined by the National Comprehensive Cancer Network [NCCN]) and at least 1 adverse clinicopathologic feature (defined as any primary Gleason pattern 5 on biopsy, clinical T3b-4 disease, ≥50% cores with biopsy results positive for prostate cancer, or NCCN ≥2 high-risk features) treated between 2000 and 2014 at 16 tertiary centers. Data were analyzed in November 2020. Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy (ADT), or EBRT plus brachytherapy boost (BT) with ADT. Guideline-concordant multimodal treatment was defined as RP with appropriate use of multimodal therapy (optimal RP), EBRT with at least 2 years of ADT (optimal EBRT), or EBRT with BT with at least 1 year ADT (optimal EBRT with BT). The primary outcome was prostate cancer-specific mortality; distant metastasis was a secondary outcome. Differences were evaluated using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression models. A total of 6004 men (median [interquartile range] age, 66.4 [60.9-71.8] years) with high-risk prostate cancer were analyzed, including 3175 patients (52.9%) who underwent RP, 1830 patients (30.5%) who underwent EBRT alone, and 999 patients (16.6%) who underwent EBRT with BT. Compared with RP, treatment with EBRT with BT (subdistribution hazard ratio [sHR] 0.78, [95% CI, 0.63-0.97]; P = .03) or with EBRT alone (sHR, 0.70 [95% CI, 0.53-0.92]; P = .01) was associated with significantly improved prostate cancer-specific mortality; there was no difference in prostate cancer-specific mortality between EBRT with BT and EBRT alone (sHR, 0.89 [95% CI, 0.67-1.18]; P = .43). No significant differences in prostate cancer-specific mortality were found across treatment cohorts among 2940 patients who received guideline-concordant multimodality treatment (eg, optimal EBRT alone vs optimal RP: sHR, 0.76 [95% CI, 0.52-1.09]; P = .14). However, treatment with EBRT alone or EBRT with BT was consistently associated with lower rates of distant metastasis compared with treatment with RP (eg, EBRT vs RP: sHR, 0.50 [95% CI, 0.44-0.58]; P < .001). These findings suggest that among patients with high-risk prostate cancer and additional unfavorable clinicopathologic features receiving guideline-concordant multimodal therapy, prostate cancer-specific mortality outcomes were equivalent among those treated with RP, EBRT, and EBRT with BT, although distant metastasis outcomes were more favorable among patients treated with EBRT and EBRT with BT. Optimal multimodality treatment is critical for improving outcomes in patients with high-risk prostate cancer.

INNOVATE (NRG-GU008): A randomized phase III trial of salvage radiotherapy and androgen deprivation therapy (ADT) with/without abiraterone and apalutamide for patients with node-positive prostate cancer after radical prostatectomy.

TPS179 Background: Node-positive prostate cancer comprises for approximately 13% of newly-diagnosed patients and represents an aggressive form of the disease, but has been historically understudied in therapeutic clinical trials. Cure rates remain suboptimal for these patients with early stage IV disease, so clinical trials to intensify systemic treatment are warranted. Abiraterone and apalutamide have each demonstrated efficacy in improving metastasis-free survival and/or overall survival in the advanced stage setting, including both castrate-resistant and metastatic castration-sensitive prostate cancer. The mechanisms of action of abiraterone and apalutamide are complementary, and combination therapy has been shown in a prior Phase Ib trial to be safe and well-tolerated. Methods: Patients with pathologic node-positive disease by radical prostatectomy and who subsequently have a detectable PSA are eligible for this randomized controlled trial. All patients are required to receive molecular imaging (FACBC, PSMA, or choline PET scan) at trial entry and must have no radiographic evidence of distant metastasis in order to remain eligible. Eligible patients are randomized 1:1 to (control arm) salvage radiation therapy with 2 years of ADT vs (experimental arm) addition of 2 years of abiraterone/prednisone and apalutamide. The primary endpoint is metastasis-free survival. With a sample size of 586 and with a potential for 10% loss to follow-up, the trial has 90% power with one-sided alpha=0.025 to detect a HR of 0.53 for the experimental arm vs control arm for the primary endpoint. Secondary endpoints include quality of life (EPIC-26, EQ5D-5L, Brief Pain Inventory, PROMIS-Fatigue), overall survival, time to castrate resistance, and other disease-related outcomes. In addition, data will be collected to validate the Decipher score and PAM50-based classification as predictive biomarkers in this node-positive patient population. Trial was activated on March 5, 2020, and is currently enrolling patients. This project was supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), U24CA196067 (NRG Oncology Specimen Bank) from the National Cancer Institute (NCI) and Janssen and GenomeDX. Clinical trial information: NCT04134260.

Association Between T-Stage and Cancer-Specific Mortality among Men with High-Risk Prostate Adenocarcinoma

Risk group stratification identifies men with high-risk prostate adenocarcinoma (Gleason 8-10, PSA > 20 ng/mL, or cT3-T4) who benefit from more intense treatment. However, many patients are classified as high-risk with only one high-risk feature. Although many trials that are the basis for 2-3 years of androgen deprivation therapy (ADT) studied patients with mostly cT3/T4 disease, PSA-detected, non-palpable T1c disease is currently the most commonly detected. We assessed whether within localized high-risk prostate cancer, survival differences existed based on T-stage. Data from men with high-risk N0M0 prostate adenocarcinoma from the 2004 to 2015 Surveillance, Epidemiology, and End Results database were used. Ten-year PCSM was estimated using Fine-Gray competing-risk regression. The independent variable of interest was clinical T-stage (cT1/2 vs. cT3/4); adjustments were made for PSA, Gleason score, treatment with radical prostatectomy (RP) and radiation (RT), and relevant demographic factors. A second analysis assessed PCSM only among men who received RP, with pathologic T-stage as co-variate (pT2 vs. pT3/4). The average of 12 prostate cancer prognostic signatures, including Decipher prostate cancer signature, compared genomic risk score by pT-stage. For 63,319 men included (median follow-up 6.4 years, median age 68 years), 56,322 (89.0%) had cT1/2, and 6,997 (11.1%) had cT3/4 disease. Ten-year PCSM for men with cT1/2 disease was 12.5%, and for men with cT3/4 disease was 17.5% (competing risk regression HR 0.55, 95CI 0.51—0.60, P<0.001). Greater PSA and greater Gleason score were associated with greater PCSM; receipt of RP, RT, being married, greater income, and later year of diagnosis were associated with lower PCSM. African American and Other race were also associated with lower PCSM. Of the 20,409 men who received radical prostatectomy, 9,953 (48.8%) had pT2 disease and 10,456 (51.2%) had pT3/4 disease. Ten-year PCSM for post-RP men with pT2 disease was 3.5%, and for men with pT3/4 disease was 11.9% (competing risk regression HR 0.29, 95CI 0.24—0.35, P<0.001). Greater PSA, Gleason score, receipt of radiation, and earlier year of diagnosis were associated with worse PCSM. Within a high-risk prospective RP cohort (n = 10,419) from the Decipher GRID registry (NCT02609269), patients with pT3/4 had significantly higher genomic risk scores than patients with pT2 (p<0.001). Men with cT1/2 disease had improved cancer-specific outcomes compared to men with cT3/4. Among men treated with RP, pT2 disease was associated with lower PCSM compared to pT3/4. Genomic risk scores validated these findings. Therefore, treatment paradigms given clinically relevant sub-classification of high-risk tumors based on size merit further study, with a focus on shorter-duration ADT among men with high-risk but T1/2 disease. As cT1c disease is most commonly diagnosed, more men with smaller tumors should be included in trials.

RTOG 3506 (STEEL): A study of salvage radiotherapy with or without enzalutamide in recurrent prostate cancer following surgery.

TPS5601 Background: Salvage radiotherapy (SRT) is an important intervention for men with prostate cancer (PCa) who experience biochemical recurrence (BCR) after radical prostatectomy (RP). These patients are in need of cure or else they will develop metastatic disease. NRG/RTOG 9601 (WU Shipley, N Eng J Med 2017) identified a survival benefit from the addition of androgen receptor (AR) inhibition to SRT that was most prominent in men with high-risk features. Enzalutamide (Enza) is a non-steroidal anti-androgen that improves survival in castration-resistant and -sensitive PCa. We hypothesized that enhanced AR suppression with Enza would augment the benefit of SRT + androgen deprivation therapy (ADT) in BCR with high risk features. Methods: RTOG 3506 (STEEL, NCT03809000) is a randomized phase II study of SRT in BCR after RP with a serum PSA ≥ 0.2 ng/mL active in the USA and Canada. Patients are stratified by number of high-risk features including Gleason score (8-10), locoregional node involvement at RP, seminal vesicle invasion, persistently elevated PSA after RP, and PSA &gt; 0.7 ng/mL. All patients receive SRT with 2 years of ADT. The experimental arm also receives Enza 160 mg daily for 2 years. Patients are followed by PSA every 3 months. SRT can be highly individualized per treating physician beyond the mandatory treatment of the prostatic fossa. Treatment of the pelvis and/or para-aortic nodes, as well as sequential or concurrent boosts to a prostatic fossa mass and/or suspicious lymph nodes, are allowed options. This permits individualization of radiotherapy guided by CT, MRI, PET, and/or biopsy findings. The primary goal of this study is to determine whether SRT enhanced ADT with Enza, will improve progression-free survival (PFS) compared to SRT with standard ADT. PFS defined as the first occurrence of biochemical failure, clinical failure, or initiation of new anticancer treatment. STEEL is designed to demonstrate a 35% reduction in the risk of progression at 5 years. An accrual goal of 242 patients will provide 80% power with a one-sided alpha = 0.10. Secondary endpoints include disease control rates, acute and late physician- and patient-reported toxicity, and quality of life. This study was activated in February 2019. Site recruitment and activation are underway. Conclusions: There is an unmet and urgent need for individualized strategies to optimize systemic therapy used with SRT for men with BCR. Outcomes from this study will further clarify the approach to systemic therapy for SRT in high-risk BCR patients. Support: Provided by Pfizer. Clinical trial information: NCT03809000 .

Androgen deprivation therapy in patients with localized disease: Comparison with curative intent treatments and time to castration resistance. Results of the Spanish Prostate Cancer Registry

BackgroundThe effect of primary androgen deprivation therapy (ADT) in patients with localized prostate cancer (PCa) has not been well documented. The objective of the present study was to analyze the outcome of tumors treated with ADT as primary therapy in the Spanish Prostate Cancer Registry (19.4% of the series). Patients and methodsPatients were classified in three groups: (1) with low/intermediate risk clinically localized tumors; (2) with high risk and locally advanced (T3-4) tumors; (3) with metastatic tumors. Time to castration resistance and overall cancer-specific survival were analyzed. In non-metastatic tumors, survivals in patients treated with ADT were compared with data from patients who underwent local treatments from the Spanish Prostate Cancer Registry. Results703 cases were analyzed. There were significant differences in the time to castration resistance, which was lower in the group of metastatic tumors. During follow-up, there were 179 deaths (25.5%) of which 89 (12.6%) were due to PCa. After 3 years of ADT, only 14.6% of patients in group 1 had died (1% due to PCa), 20.5% in group 2 and 46.8% in group 3 (9.2% and 31.3% due to PCa, respectively). Cancer-specific survival was significantly worse in group 1 using ADT than radical prostatectomy or radiotherapy. In high-risk and locally advanced tumors, ADT also had a lower cancer-specific survival than local treatments. ConclusionA longer time until the castration resistance was observed in patients with well- and intermediate-risk localized tumors treated with ADT. Patients with metastatic tumors showed the shortest time to castration resistance.

Terapia de privación de andrógenos en pacientes con enfermedad localizada: comparación de las opciones de tratamiento y tiempo hasta la resistencia a la castración. Resultados del Registro Español de Cáncer de Próstata

BackgroundThe effect of primary androgen deprivation therapy (ADT) in patients with localized prostate cancer (PCa) has not been well documented. The objective of the present study was to analyze the outcome of tumors treated with ADT as primary therapy in the Spanish Prostate Cancer Registry (19.4% of the series). Patients and methodsPatients were classified in three groups: 1) with low/intermediate risk clinically localized tumors; 2) with high risk and locally advanced (T3-4) tumors; 3) with metastatic tumors. Time to castration resistance and overall cancer-specific survival were analyzed. In non-metastatic tumors, survivals in patients treated with ADT were compared with data from patients who underwent local treatments from the Spanish Prostate Cancer Registry. Results703 cases were analyzed. There were significant differences in the time to castration resistance, which was lower in the group of metastatic tumors. During follow-up, there were 179 deaths (25.5%) of which 89 (12.6%) were due to PCa. After 3 years of ADT, only 14.6% of patients in group 1 had died (1% due to PCa), 20.5% in group 2 and 46.8% in group 3 (9.2% and 31.3% due to PCa, respectively). Cancer-specific survival was significantly worse in group 1 using ADT than radical prostatectomy or radiotherapy. In high-risk and locally advanced tumors, ADT also had a lower cancer-specific survival than local treatments. ConclusionA longer time until the castration resistance was observed in patients with well- and intermediate-risk localized tumors treated with ADT. Patients with metastatic tumors showed the shortest time to castration resistance.

Late toxicity and quality of life with prostate only or whole pelvic radiation therapy in high risk prostate cancer (POP-RT): A randomised trial

AimTo report toxicity and quality of life (QOL) outcomes from a randomised trial of prostate only versus whole pelvic radiotherapy in high risk, node negative prostate cancer. Materials/methodsPatients with localised prostate adenocarcinoma and nodal involvement risk > 20%, were randomised to prostate only (PORT, 68 Gy/25# to prostate) and whole pelvis (WPRT, 68 Gy/25# to prostate and 50 Gy/25# to pelvis) arms with stratification for TURP, Gleason score, baseline PSA, and type of androgen deprivation therapy (ADT). Image guided intensity modulated radiotherapy (IG-IMRT) and two years of ADT were mandatory. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicities were graded using RTOG grading. QOL was assessed using EORTC QLQ-C30 and PR-25 questionnaire pre-treatment and every 3–6 months post RT. ResultsTotal 224 patients were randomised (PORT 114, WPRT 110) from November 2011 to August 2017. Median follow up was 44.5 months. No RTOG grade IV toxicity was observed. Acute GI and GU toxicities were similar between both the arms. Cumulative ≥ grade II late GI toxicity was similar for WPRT and PORT (6.5% vs. 3.8%, p = 0.39) but GU toxicity was higher (17.7% vs. 7.5%, p = 0.03). Dosimetric analysis showed higher bladder volume receiving 30–40 Gy in the WPRT arm (V30, 60% vs. 36%, p < 0.001; V40, 41% vs. 25%, p < 0.001). There was no difference in QOL scores of any domain between both arms. ConclusionPelvic irradiation using hypofractionated IG-IMRT resulted in increased grade II or higher late genitourinary toxicity as compared to prostate only RT, but the difference was not reflected in patient reported QOL. Clinicaltrials.gov NCT02302105Prostate Only or Whole Pelvic Radiation Therapy in High Risk Prostate Cancer (POP-RT).

The Clinical Significance of Bone Mineral Density Changes Following Long Term Androgen Deprivation Therapy in Prostate Cancer Patients Enrolled in the PCS V Trial

Treatment for advanced prostate cancer includes long term androgen deprivation therapy (ADT), which has been associated with decreased bone mineral density (BMD). It is unclear whether this translates to a clinically significant change in bone density status. Some evidence suggests that there is no impact on fracture risk despite a decrease in BMD. We quantified changes in BMD when all patients on ADT were mandated to take Calcium and Vitamin D (CaVitD) in the setting of a phase III randomized clinical trial and compared the findings to historical data. BMD analysis was conducted for high-risk prostate cancer patients enrolled in the PCS V study (NCT01444820), a randomized phase III trial comparing conventional and hypofractionated radiotherapy regimens. Patients received 24 months of ADT and were prescribed CaVitD supplementation (Carbocal D 1 tablet twice daily; 500mg of Calcium + 400 IU of Vitamin D3). Long-course ADT consisted of luteinizing hormone-releasing hormone agonist therapy, with 14 days of bicalutamide (50 mg per day) with the first injection only. BMD reports at baseline and at 30 months of follow-up had the areal density and T-scores (spine, femoral neck, and total femur) extracted and the absolute change calculated. The results were then compared to the BMD decline of CaVitD control groups in bisphosphonate trials. Clinical bone density status (normal, osteopenia, versus osteoporosis) was monitored. In total, BMD reports were obtained from 329 patients. Patient data was further analyzed if a 24-month follow-up BMD data was present for a given site - 226 (spine), 231 (femoral neck), and 173 (total femur). The mean change (standard deviation) in the areal density was -2.65% (5.78), -2.76% (5.59), -4.27% (4.41), respectively. The difference was statistically significant for all three sites (p<0.001). The average decrease in BMD across all three sites was -3.2% after 24 months of ADT, compared to a historical figure of -2.1% following 12 months of ADT. For most patients (n=140, 83%), there was no clinically significant decline in bone density status. Eight patients (5%) with osteopenia prior to ADT became osteoporotic, 18 patients (11%) who had normal BMD became osteopenic, and no patients with normal BMD developed osteoporosis. In comparison to historical data for one year of ADT, our analysis of the prospectively collected BMD data showed minimal further deterioration with two years of ADT. Despite the drop in BMD, the change in bone density status remains low. This is in accordance with data from bisphosphonate trials using CaVitD as a control group, which showed that there is no clinically significant difference in fracture risk despite changes in BMD. As such, mandating patients to take CaVitD alone while on prolonged ADT may suffice, and we propose that steps should be taken to standardize dosing and encourage patient compliance.

Suppressive Role of Androgen/Androgen Receptor Signaling via Chemokines on Prostate Cancer Cells.

Androgen/androgen receptor (AR) signaling is a significant driver of prostate cancer progression, therefore androgen-deprivation therapy (ADT) is often used as a standard form of treatment for advanced and metastatic prostate cancer patients. However, after several years of ADT, prostate cancer progresses to castration-resistant prostate cancer (CRPC). Androgen/AR signaling is still considered an important factor for prostate cancer cell survival following CRPC progression, while recent studies have reported dichotomic roles for androgen/AR signaling. Androgen/AR signaling increases prostate cancer cell proliferation, while simultaneously inhibiting migration. As a result, ADT can induce prostate cancer metastasis. Several C-C motif ligand (CCL)-receptor (CCR) axes are involved in cancer cell migration related to blockade of androgen/AR signaling. The CCL2-CCR2 axis is negatively regulated by androgen/AR signaling, with the CCL22-CCR4 axis acting as a further downstream mediator, both of which promote prostate cancer cell migration. Furthermore, the CCL5-CCR5 axis inhibits androgen/AR signaling as an upstream mediator. CCL4 is involved in prostate carcinogenesis through macrophage AR signaling, while the CCL21-CCR7 axis in prostate cancer cells is activated by tumor necrotic factor, which is secreted when androgen/AR signaling is inhibited. Finally, the CCL2-CCR2 axis has recently been demonstrated to be a key contributor to cabazitaxel resistance in CRPC.

Phase 2 Randomized Study of Radiation Therapy and 3-Year Androgen Deprivation With or Without Concurrent Weekly Docetaxel in High-Risk Localized Prostate Cancer Patients

Docetaxel improves survival in patients with metastatic prostate cancer. This randomized phase 2 trial aimed to assess the activity of weekly docetaxel with radiation therapy (RT) plus androgen deprivation in patients with high-risk localized prostate cancer. The study examined the benefit of 9 weekly docetaxel administrations to RT plus 3years of luteinizing hormone-releasing hormone analogues. A total of 132 patients were recruited for the study. Patients' characteristics included T3-T4 stage (81.1%), Gleason score ≥8 (77.3%), prostate-specific antigen level >20ng/mL (28.9%), and pN+ (18.2%). All patients included in the trial received either the standard-of-care control arm with luteinizing hormone-releasing hormone analogues plus RT (arm A) or the experimental arm (RT+9 weekly cycles of docetaxel+3years of androgen deprivation therapy, arm B). The primary objective was to achieve a high percentage of patients who were free of biochemical recurrence within 5years of randomization. Secondary endpoints included biochemical recurrence-free survival (BRFS), progression-free survival (PFS), overall survival (OS), clinical response rate, biochemical response rate, and toxicity. No difference between the arms of the study was found in biochemical recurrence (93.4% at 60months for arm A vs 85.3% for arm B; P=.3297). PFS at 60months was 93.4% and 83.7% in arms A and B, respectively (P=.2532). Five-year survival was 93.3% (95% confidence interval, 83.1-97.45) in arm A versus 93.6% (83.8-97.55) in arm B; median PFS and OS have not been reached. Prostate-specific antigen level ≤0.2ng/mL at 3months after the end of treatment was seen in 81.25% of patients in arm A compared with 90.48% of patients in arm B (P=.2028). BRFS was not significantly different between treatment arms. Diarrhea was the main nonhematologic toxicity. Long-term follow-up has not yet been enough to meet median PFS and OS. Concurrent weekly docetaxel can be administered safely with standard doses of RT without a significant increase in the toxicity profile. No statistically significant differences for 5-year BRFS, PFS, and OS have been observed when docetaxel was added to conventional treatment.