Androgen Deprivation Therapy For Prostate Cancer Research Articles

Home-based versus supervised group exercise in men with prostate cancer on androgen deprivation therapy: A randomized controlled trial and economic analysis

IntroductionDifferences between health outcomes, participation/adoption, and cost-effectiveness of home-based (HOME) interventions and supervised group-based training (GROUP) in men with prostate cancer (PC) on androgen deprivation therapy (ADT) are currently unknown. The objective of this study was to assess the clinical efficacy, adherence, and cost-effectiveness of HOME versus GROUP in men on ADT for PC. Materials and MethodsThis was a multicentre, 2-arm non-inferiority randomized controlled trial and companion cost-effectiveness analysis. Men with PC on ADT were recruited from August 2016 to March 2020 from four Canadian centres and randomized 1:1 to GROUP or HOME. All study participants engaged in aerobic and resistance training four to five days weekly for six months. Fatigue [Functional Assessment of Cancer Therapy-Fatigue (FACT-F)] and functional endurance [6-min walk test (6MWT)] at six months were the co-primary outcomes. Secondary outcomes included quality of life, physical fitness, body composition, blood markers, sedentary behaviour, and adherence. Between-group differences in primary outcomes were compared to margins of 3 points for FACT-F and 40 m for 6MWT using a Bayesian analysis of covariance (ANCOVA). Secondary outcomes were compared with ANCOVA, Costs included Ministry of Health costs, program costs, patient out-of-pocket, and time costs. Trial Registration: #NCT02834416. ResultsThirty-eight participants (mean [standard deviation (SD)] age, 70 [9.0] years) were enrolled (GROUP n = 20; HOME n = 18). There was an 89.8% probability that HOME was non-inferior to GROUP for both fatigue and functional endurance and a 9.5% probability that HOME reduced fatigue compared to GROUP (mean [SD] change, 12.1 [8.1] vs 3.6 [6.1]; p = 0.040) at six months. Adherence was similar among study arms. HOME was cost-saving (mean difference: -$4122) relative to GROUP. DiscussionA HOME exercise intervention appears non-inferior to GROUP for fatigue and functional endurance and requires fewer resources to implement. HOME appears to ameliorate fatigue more than GROUP, but has comparable effects on other clinically relevant outcomes. Although limited by sample size and attrition, these results support further assessment of home-based programs.

Management of cancer treatment-induced bone loss (CTIBL) in patients with breast cancer or prostate cancer.

Breast cancer and prostate cancer are sex hormone-dependent cancers, and estrogen or androgen suppression therapy is the standard treatment. Cancer treatment-induced bone loss (CTIBL): bone loss and osteoporosis have become important side effects of these therapies. To summarize the current evidences, (1) Endocrine therapy for breast cancer and prostate cancer is associated with a significant decrease in bone mineral density. (2) Aromatase inhibitors (AI) for breast cancer are associated with a significant increase in fractures, and androgen deprivation therapy (ADT) for prostate cancer is likely to be associated with an increase in fractures. (3) Administration of bisphosphonates and denosumab increases bone mass in patients undergoing endocrine therapy for breast cancer. Administration of bisphosphonates, denosumab, and SERMs increased bone mass in patients undergoing ADT therapy for prostate cancer. (4) Bisphosphonates and denosumab reduce fracture risk in patients on AI for breast cancer, and toremifene and denosumab in patients on ADT for prostate cancer.

Abstract 6542: Detection of androgen receptor splice variants from clinical sequencing

Abstract Androgen receptor (AR) splice variants (AR-Vs) have been widely studied on its important role in prostate cancer (PC) progression. In particular, AR-Vs lacking ligand binding domains, such as AR splice variant 7 (AR-v7) that links exon 3 and cryptic exon 3 or AR variant that losses exons 5 to 7 (ARv567es), have been demonstrated as one of the resistant mechanisms to androgen deprivation therapy in PC. Despite its clinical importance, the current algorithms to detect fusions such as TopHat-Fusion have limitation to detect intra-chromosomal rearrangements including AR-Vs. In this respect, we propose a novel approach to identify AR-Vs from targeted RNA sequencing (RNA-seq) dataset. In short, our two-step approach first gathers soft-clipped or divided reads that are adjacent to the splicing sites of AR-Vs and then yields the number of splitting reads that support the existence of AR-Vs. Next, the algorithm selects the paired-end reads whose one side and the other side are mapped to the preceding and following exons, respectively. The final number of spanning reads are calculated following to the removal of low-quality reads. We validated the proposed approach using two large-scale, independent RNA-seq datasets of PC samples: 34 samples from Seoul National University Hospital (SNUH) and 558 samples from The Cancer Genome Atlas (TCGA) dataset. Overall, our approach successfully identified samples with putative AR-Vs, including AR-v7 and ARv567es. In addition, our approach successfully detected AR-v7 with reliable number of supporting reads, from the RNA-seq dataset of AR-v7-expressing cell line. Finally, statistical analyses of 34 SNUH PC patients suggested potential detection threshold in clinical sequencing settings (at least 10 split reads and 1% proportion). In the SNUH dataset, The AR-v7 positive group, which included 6 patients (17.1%) with values above the threshold, had higher AR-v7 expression levels than the negative group (p=4.8E-04). The similar pattern was also found in the analysis of TCGA dataset. Owing to its flexibility, we also confirmed that the developed approach can be used to detection of other AR-Vs, including AR-v3 and ARv567es. We expect that the further in-depth analyses including larger samples and clinical outcomes can discover clinical applicability of AR-Vs. Citation Format: Suhyun Hwangbo, Sungyoung Lee, Sheehyun Kim, Hongseok Yun. Detection of androgen receptor splice variants from clinical sequencing [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 6542.

PTEN loss is not a determinant of time to castration-resistance following androgen-deprivation therapy in prostate cancer: a study from Jordan.

Androgen deprivation therapy (ADT) remains the principal treatment of advanced prostate cancer. However, most patients eventually experience treatment failure, resulting in castrate-resistant prostate cancer (CRPC). Loss of the tumor suppressor gene phosphatase and tensin homolog (PTEN) has been linked to poor survival in prostate cancer. We have recently shown that PTEN loss is evident in approximately 60% of prostate cancer cases in Jordan. However, the correlation between PTEN loss and response to ADT remains unclear. This study aimed to determine the relationship between PTEN loss and time to CRPC in Jordan. We conducted a retrospective analysis of confirmed CRPC cases at our institution from 2005 to 2019 (N=104). PTEN expression was assessed using immunohistochemistry. Time to CRPC was calculated from the initiation of ADT to the confirmed diagnosis of CRPC. Combination/sequential ADT was defined as the use of two or more classes of ADT concomitantly or switching from one class to another. We found that PTEN loss was evident in 60.6% of CRPC. Mean time to CRPC was not different between patients with PTEN loss (24.8 months) and those with intact PTEN (24.2 months; p=0.9). However, patients receiving combination/sequential ADT had a significantly delayed onset of CRPC compared to patients on monotherapy ADT (log-rank Mantel-Cox p=0.000). In conclusion, PTEN loss is not a major determinant of time to CRPC in Jordan. The use of combination/sequential ADT procures a significant therapeutic advantage over monotherapy regimens, delaying the onset of CRPC.

MP29-08 RISK OF NEUROCOGNITIVE DISORDERS IN PROSTATE CANCER ON ANDROGEN DEPRIVATION THERAPY: A META-ANALYSIS

You have accessJournal of UrologyCME1 Apr 2023MP29-08 RISK OF NEUROCOGNITIVE DISORDERS IN PROSTATE CANCER ON ANDROGEN DEPRIVATION THERAPY: A META-ANALYSIS David E. Hinojosa-Gonzalez, Affan Zafar, and Dimitar V. Zlatev David E. Hinojosa-GonzalezDavid E. Hinojosa-Gonzalez More articles by this author , Affan ZafarAffan Zafar More articles by this author , and Dimitar V. ZlatevDimitar V. Zlatev More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003257.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Androgen Deprivation Therapy (ADT) is used to treat select localized prostate cancer, biochemical recurrence and overt metastatic cancer. Androgens play a role in maintaining synaptic density, neuronal plasticity and beta-amyloid degradation. Cognitive decline and dementia due to ADT have been proposed as possible long-term consequences. This study aims to analyze the currently available evidence for the risk of dementia and other neurocognitive disorders in patients receiving ADT. METHODS: In February 2022, a systematic search was performed according to PRISMA guidelines, querying databases for “Androgen Deprivation Therapy”, “Prostate Cancer”, AND “Dementia”, “Alzheimer’s disease”(AD), and “vascular dementia”(VD). Data was analyzed in Review Manager V 5.4.2(Cochrane). Heterogeneity was assessed using Higgins I2%. RESULTS: A total of 22 studies were included, which provided 2,413,131 patients, of which 846,394 had prostate cancer and received ADT. Our analysis found an increased risk of dementia (all-cause) (HR 1.21[1.11,1.31] p<0.00001), AD (HR 1.26[1.10,1.43], p=0.0007, depression (HR 1.87 [1.74,2.00], p<0.00001), and Parkinson’s disease (HR 1.57[1.31,1.88], p<0.00001). Risk for vascular dementia was increased but not statistically significant (HR 1.30 [0.97,1.73], p=0.08). Subgroup performed by type of ADT demonstrated an increased risk of dementia for orchiectomy (HR1.36 [1.17,1.59] p < 0.0001), antiandrogens (HR 1.15 [1.07,1.23] p<0.0001) and GnRH Agonists (HR 1.11 [ 1.05,1.17] p = 0.0002). Subgroup analysis by treatment duration demonstrated an increased risk of dementia regardless of duration. CONCLUSIONS: Meta-analysis of the currently available clinical literature demonstrates that ADT for prostate cancer is associated with a significantly increased risk of dementia, AD, PD, and depression. Further studies are needed to better characterize the interaction of ADT, aging and the underlying prostatic malignancy. Source of Funding: No funding was received. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e383 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information David E. Hinojosa-Gonzalez More articles by this author Affan Zafar More articles by this author Dimitar V. Zlatev More articles by this author Expand All Advertisement PDF downloadLoading ...

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.

Using a Further Planning MRI after Neoadjuvant Androgen Deprivation Therapy Significantly Reduces the Radiation Exposure of Organs at Risk in External Beam Radiotherapy of Prostate Cancer.

Radiotherapy for prostate cancer is often preceded by neoadjuvant androgen deprivation therapy (ADT), which leads to a reduction in the size of the prostate. This study examines whether it is relevant for treatment planning to acquire a second planning magnetic resonance imaging (MRI) after ADT (=MRI 2) or whether it can be planned without disadvantage based on an MRI acquired before starting ADT (=MRI 1). The imaging data for the radiotherapy treatment planning of 17 patients with prostate cancer who received two planning MRIs (before and after neoadjuvant ADT) were analyzed as follows: detailed comparable radiation plans were created separately, each based on the planning CT scan and either MRI 1 or MRI 2. After ADT for an average of 17.2 weeks, the prostate was reduced in size by an average of 24%. By using MRI 2 for treatment planning, the V60Gy of the rectum could be significantly relieved by an average of 15% with the same coverage of the target volume, and the V70Gy by as much as 33% (compared to using MRI 1 alone). Using a second MRI for treatment planning after neoadjuvant ADT in prostate cancer leads to a significant relief for the organs at risk, especially in the high dose range, with the same irradiation of the target volume, and should therefore be carried out regularly. Waiting for the prostate to shrink after a few months of ADT contributes to relief for the organs at risk and to lowering the toxicity. However, the use of reduced target volumes requires an image-guided application, and the oncological outcome needs to be verified in further studies.

Concurrent Androgen Deprivation Therapy for Prostate Cancer Improves Survival for Synchronous or Metachronous Non-Small Cell Lung Cancer: A SEER-Medicare Database Analysis.

Simple SummaryThe study showed that androgen deprivation therapy for a preceding diagnosis of prostate cancer is associated with prolonged survival among patients who subsequently develop lung cancer. These population-level findings support a role of the androgen receptor in lung cancer.Introduction: The crosstalk between receptor kinase signaling, such as EGFR and androgen receptor signaling, suggests a potential interaction between androgen deprivation therapy (ADT) and lung cancer outcome. Methods: We employed the SEER–Medicare data of lung cancer patients diagnosed between 1988 and 2005 to test for an association between ADT for prostate cancer and lung cancer outcome. We employed the Kaplan–Meier method and Cox proportional hazard with log-rank test model to assess any significant impact of ADT on survival. Results: We included data from 367,750 lung cancer patients; 17.4%, 2.9%, 33.6% and 46.1% with stages I, II, III and IV, respectively; 84.5% were >65 years; 57.2% males; 84.2% Caucasians and 9.3% Blacks. There were 11,061 patients (3%) with an initial prostate cancer diagnosis followed by lung cancer (P-L group); 3017 (0.8%) with an initial diagnosis of lung cancer and subsequent prostate cancer diagnosis (L-P group); the remainder had only lung cancer (L group). Stage I lung cancer was most common in the L-P group compared to the L and P-L groups—54% vs. 17.13% vs. 17.92%, p < 0.0001 for L-P, L and P-L, respectively. The median OS for lung cancer diagnosis was 93 months versus 10 and 9 months, respectively, for the L-P, L and P-L subgroups. ADT was associated with improved survival on multivariate analysis, especially in Caucasian patients (HR of death: 0.86; 95% CI: 0.76–0.97; p = 0.012). Conclusion: ADT was associated with improved outcome for NSCLC, in line with the hypothesis of a role for the androgen receptor in lung cancer. Our findings support a systematic evaluation of the potential benefit of ADT as a therapy for lung cancer.

Association between medical androgen deprivation therapy and long-term cardiovascular disease and all-cause mortality in nonmetastatic prostate cancer.

Studies have suggested that prostate cancer (PCa) patients receiving androgen deprivation therapy (ADT) are at increased risk of developing or exacerbating cardiovascular disease (CVD). We aimed to explore the association between ADT for PCa and subsequent CVD and all‐cause mortality in this nationwide, longitudinal study. We also evaluated the role of cardiovascular risk and ADT duration to determine effect modification. Norwegian registry data were used to identify patients with PCa from 2008‐18 and who received primary ADT in the first year after diagnosis. The associations between ADT and composite cardiovascular events, and the individual components of myocardial infarction, stroke and heart failure, in addition to atrial fibrillation and all‐cause mortality, were explored using time‐varying Cox regression models. We included 30 923 PCa patients, of whom 8449 (27%) received primary ADT. Mean follow‐up was 2.9 and 3.8 years for CVD events and mortality, respectively. We found an association between ADT and composite CVD (adjusted HR 1.13: 95% CI 1.05‐1.21), myocardial infarction (1.18: 1.05‐1.32), stroke (1.21: 1.06‐1.38), heart failure (1.23: 1.13‐1.35) and all‐cause mortality (1.49: 1.39‐1.61). These associations persisted in those with low and moderate CVD risk and ADT longer than 7 months. A relationship between ADT and composite CVD and all‐cause mortality was observed, especially in those with moderate CVD risk and longer treatment duration. Future studies with more detailed cancer data are needed to verify the clinical relevance of these results, especially when considering all‐cause mortality within the context of treatment guidelines and benefits of ADT.

A randomized, controlled trial of group exercise training for fall prevention and functional improvements during and after treatment for prostate cancer.

TPS193 Background: Many prostate cancer survivors are treated with androgen deprivation therapy (ADT), but these therapies may increase frailty, worsen physical functioning, and increase fall risk. While exercise may counter functional declines associated with ADT, no studies have tested whether and which type of exercise may reduce falls and frailty. The purpose of this trial is to compare the relative efficacy of strength training versus tai ji quan training against each other and to a stretching control group on falls, frailty and physical functioning in men expose to ADT for prostate cancer. Methods: Prostate cancer survivors treated with ADT (n = 360) will be recruited to participate in this single-blind, parallel group, randomized trial. To be eligible men must meet the following criteria: 1) histologically confirmed prostate cancer, 2) received at least 6 months of ADT within the past 10 years, 3) report &gt;1 fall in the past year OR have a score on one of two physical performance tests that is associated with increased fall risk (i.e. ≥ 12.0 seconds to complete the 3 meter timed up and go (TUG), or ≥ 10.0 seconds to complete 5 chair stands), 4) completed any other treatment at least 6 weeks prior to enrollment and not be on any concurrent prostate cancer therapy besides ADT, 5) not currently participating in moderate-vigorous intensity lower-body strength training or tai ji quan training ≥ 2 times/week for ≥ 30 minutes per session, 6) no cognitive difficulties that limit ability to answer survey questions or participate in exercise classes and performance tests, 7) no medical condition, disorder, or take medication that contraindicates participation in moderate intensity exercise, and 8) are able to communicate in English. Participants will be randomized to one of three supervised, group training programs: i) strength training, ii) tai ji quan training, or iii) stretching (control), that train 3x/week for 6 months. Outcomes are assessed at baseline, 3 (mid-intervention), 6 (immediately post-intervention) and 12 (follow-up) months. The primary outcome is falls assessed by monthly self-report. Secondary outcomes include the following: Frailty (low lean body mass (by bioelectrical impedance analysis), exhaustion (by SF-36 vitality scale), low activity (by CHAMPS physical activity survey), slowness (by 4m usual walk speed), and weakness (by chair stand time)); Objective and subjective measures of physical function will also be collected. Negative binomial regression models will be used to assess differences in falls between groups, while mixed-effects modeling will be used to compare the relative efficacy of training group on secondary outcomes. Registered November 18, 2018. Clinical trial information: NCT03741335.

Androgen Deprivation Therapy for Prostate Cancer Did Not Increase the Risk of Retinal Vascular Occlusion: A Population-Based Cohort Study.

This study aimed to evaluate the effect of androgen deprivation therapy (ADT) on retinal vascular occlusion (RVO) development in patients with prostate cancer, using data from Taiwan’s National Health Insurance Research Database. A total of 1791, 1791, and 3582 patients were enrolled in the prostate cancer with ADT group, prostate cancer without ADT group, and the control group, respectively. The primary outcome was RVO occurrence, according to diagnostic codes. Cox proportional hazard regression was used to determine the adjusted hazard ratio (aHR) and 95% confidence interval (CI) of ADT and other covariates for RVO incidence. After a follow-up interval of up to 18 years, the patients with prostate cancer who received ADT showed significantly lower RVO incidence than the control group (aHR: 0.191, 95% CI: 0.059–0.621, p = 0.0059), after adjusting for multiple confounders. Hypertension was related to higher RVO incidence (aHR: 2.130, 95% CI: 1.127–4.027, p = 0.0199). Our overall results showed that using ADT for prostate cancer did not lead to a greater risk of RVO development. In fact, the patients with prostate cancer who received ADT had lower RVO incidence than those who did not receive ADT.

Gonadotropin-releasing hormone agonists in prostate cancer: A comparative review of efficacy and safety

Androgen deprivation therapy (ADT) using gonadotropin-releasing hormone agonist (s) (GnRH-A) remains the backbone of advanced prostate cancer treatment. In this review, we assessed the efficacy, safety, and convenience of administration of various GnRH-A. All GnRH-A (goserelin, triptorelin, buserelin, histrelin, and leuprorelin) have comparable potential to suppress testosterone (T) levels (≤50 ng/dL in a month and ≤20 ng/dL in 3 months). However, goserelin has shown better efficacy in maintaining T levels ≤50 ng/dL compared with leuprolide. The incidences of T escape are lower with goserelin and leuprolide than buserelin. Goserelin also has maximum benefit in prostate-specific antigen suppression. In neoadjuvant setting, when only goserelin was used, the 10-year overall survival (OS) rate was 42.6% to 86%. When either goserelin or leuprolide was used, the 10-year OS rate was 62%. As an adjuvant to radical prostatectomy, goserelin had a 10-year survival rate of 87%, and triptorelin had an 8-year survival rate of 84.6%. Goserelin further showed an absolute survival rate of 49% when used as an adjuvant to radiotherapy. The survival rates further improved when GnRH-A are used as combined androgen blockade compared with monotherapy. The frequency and severity of adverse events (hot flushes, fatigue, sexual dysfunction) are comparable among the GnRH-A. Goserelin appears to be the most convenient of all the GnRH-A for administration. Lack of conclusive comparative evidence makes it imperative to have a holistic approach of considering the patient profile and the disease characteristics to select the appropriate GnRH-A for ADT in prostate cancer.

Androgen deprivation therapy and acute kidney injury in patients with prostate cancer undergoing definitive radiotherapy.

Androgen deprivation therapy (ADT) is frequently utilized in conjunction with radiotherapy (RT) in the definitive management of prostate cancer. Prior studies have suggested an association between ADT use and acute kidney injury (AKI), however, these included heterogeneous populations undergoing a variety of treatments and relied on billing codes to ascertain the incidence of AKI. We analyzed a cohort of 27,868 veterans undergoing definitive RT + /- ADT for prostate cancer between 2001 and 2015 using the Veterans Affairs Informatics and Computing Infrastructure (VINCI). Exposure was defined as use of ADT within one year of diagnosis. The primary outcome was AKI, defined by an increase in serum creatinine to at least 1.5 times the baseline value. AKIs were classified as mild, moderate, or severe in accordance with international guidelines. A multivariate competing risks model was used to account for demographic and oncologic factors as well as medications and procedures known to influence the risk of AKI. Most (n = 18,754) men received RT alone; 9,114 men received RT + ADT. The incidence of AKI at two years after diagnosis was 10.5% in the RT + ADT group and 7.9% in the RT group (Gray's test p < 0.01). Multivariate analysis confirmed ADT usage was associated with an increased risk for any AKI (SHR = 1.24, 95% CI = 1.14-1.36, p < 0.01). ADT was also associated with an increased risk of mild AKI (SHR = 1.13, 95% CI = 1.01-1.27, p = 0.04) and moderate AKI (SHR = 1.45, 95% CI = 1.20-1.76, p < 0.01), though not severe AKI (SHR = 1.33, 95% CI = 0.93-1.91, p = 0.11). Our findings confirm that use of ADT is associated with an increased risk of AKI in patients undergoing definitive RT for prostate cancer. Clinicians should be alert to the potential for renal dysfunction in this population.

Differential Impact of TGFB1 Variation by Metastatic Status in Androgen-Deprivation Therapy for Prostate Cancer.

Transforming growth factor-β1 (TGF-β1) plays a dual role in cancer, acting as a tumor suppressor in the early stage of cancer development and as a tumor promoter in the later stage of cancer progression in various cancers. In this study, we investigated the association between genetic polymorphisms in TGFB1 and clinicopathological characteristics or oncological outcome in prostate cancer cases treated with androgen-deprivation therapy (ADT) according to metastasis status. Japanese male patients with hormone-sensitive prostate cancer treated with ADT from 1993 to 2005 were included in this study. Genomic DNA was obtained from whole blood samples, and genotyping of TGFB1 (rs2241716 and rs4803455) was performed by PCR-based technique. No significant association between genetic polymorphisms in TGFB1 (rs2241716 and rs4803455) and clinicopathological parameters or prognosis was observed in patients with non-metastatic disease. In patients with metastatic disease, Gleason score in CT/TT carriers (rs2241716) and CA/AA carriers (rs4803455) was unfavorable compared with CC carriers. In addition, the CT/TT alleles in rs2241716 (hazard ratio, 1.82; 95% confidence interval, 1.12–2.94; P = 0.015) and the CA/AA alleles in rs4803455 (hazard ratio, 1.75; 95% confidence interval, 1.03–2.98; P = 0.040) were associated with a higher risk of progression during ADT compared with the CC allele in patients with metastatic disease. TGFB1 genetic variations were associated with adverse characteristics and progression risk in ADT among patients with metastatic disease, but not those with non-metastatic disease, supporting a distinct role of TGF-β signaling between non-metastatic and metastatic prostate cancer.

Comprehensive Lifestyle Improvement Program for Prostate Cancer (CLIPP) is associated with improvement in weight and components of metabolic syndrome in men exposed to androgen deprivation therapy for prostate cancer.

Androgen deprivation therapy (ADT) for prostate cancer is associated with adverse effects, such as obesity and metabolic syndrome, which increase cardiovascular risk, the most common cause of non-cancer mortality in men diagnosed with prostate cancer. The Comprehensive Lifestyle Improvement Program for Prostate Cancer (CLIPP) was created to determine the feasibility of conducing a comprehensive lifestyle modification intervention in men on ADT for prostate cancer and determine its early efficacy in reducing obesity and metabolic syndrome. A single-arm, open-label clinical trial was conducted by recruiting 31 men diagnosed with prostate cancer and exposed to ADT within the last 5 years. A multicomponent lifestyle modification program was delivered weekly for 16 weeks by a trained health coach. This was followed by 8 weeks of passive follow-up resulting in a total trial duration of 24 weeks. Feasibility was determined by calculating study recruitment, retention, and adherence rates. Weight and components of metabolic syndrome (waist circumference, triglycerides (TG), high-density lipoprotein (HDL), serum glucose, and blood pressure (BP)) were measured at baseline, 12, and 24 weeks. Recruitment, retention, and adherence rates were 47.1%, 90.3%, and 100%, respectively. Statistically significant improvements were noted between baseline and end of study measurements for weight (206.3 vs. 191.3 lbs, p < 0.001), waist (41.3 vs. 38.8 inches, p < 0.001), systolic BP (144.1 vs. 133.4 mm of Hg, p = 0.014), diastolic BP (83.3 vs. 76.2 mm of Hg, p = 0.0056), TG (146.0 vs. 113.8 mg/dl, p = 0.022), HDL (51.1 vs. 55.0 mg/dl, p = 0.012), and serum glucose (114.0 vs. 103.2 mg/dl, p = 0.013). CLIPP demonstrates feasibility and early efficacy of a multicomponent lifestyle modification intervention toward addressing obesity as well as components of metabolic syndrome in men on ADT for prostate cancer. This study provides strong preliminary data to develop future clinical trials in this population.

A Phase 1 study Combining Pexidartinib, Radiation Therapy, and Androgen Deprivation Therapy in Men With Intermediate- and High-Risk Prostate Cancer

PurposeThis study aimed to evaluate a combination of radiation therapy (RT), androgen deprivation therapy (ADT), and pexidartinib (colony-stimulating factor 1 receptor [CSF1R]) inhibitor in men with intermediate- and high-risk prostate cancer. CSF1R signaling promotes tumor infiltration and survival of tumor-associated macrophages, which in turn promote progression and resistance. Counteracting protumorigenic actions of tumor-associated macrophages via CSF1R inhibition may enhance therapeutic efficacy of RT and ADT for prostate cancer. Methods and MaterialsIn this phase 1 study, the treatment regimen consisted of pexidartinib (800 mg, administered as a split-dose twice daily) and ADT (both for a total of 6 months), and RT that was initiated at the start of month 3. RT volumes included the prostate and proximal seminal vesicles. The delivered dose was 7920 cGy (180 cGy per fraction) using intensity modulated RT with daily image guidance for prostate localization. The primary objective was to identify the maximum tolerated dose based on dose-limiting toxicities. ResultsAll 4 enrolled patients who were eligible to receive RT had T1 stage prostate cancer, 2 were intermediate risk, and 2 were high risk. The median age was 62.5 years, and the prostate-specific antigen levels were in the range 6.4 to 10.7 ng/mL. The patients’ individual Gleason scores were 3 + 3, 4 + 3, 4 + 4, and 4 + 5. All 4 patients reported ≥1 adverse events before RT. Grade 1 hypopigmentation was observed in 1 patient, and grade 3 pulmonary embolus in another. One patient experienced fatigue and joint pain, and another elevated amylase and pruritus (all grade 3 toxicities). Five of the 6 adverse events noted in 3 patients were all grade 3 toxicities attributable to pexidartinib, qualifying as dose-limiting toxicities and ultimately resulting in the study closure. ConclusionsThe combination was not well tolerated and does not warrant further investigation in men with intermediate- and high-risk prostate cancer.

Resistance to Antiandrogens in Prostate Cancer: Is It Inevitable, Intrinsic or Induced?

Simple SummaryBiochemical inhibition of male sex hormone function (androgen signaling), also known as androgen deprivation therapy (ADT), for human prostate cancer remains a major treatment strategy almost 80 years after the discovery of androgens as a major factor in the disease. Drug development has resulted in an increasing potency, whereas the understanding of the consequences of these new-generation inhibitors in cancer survivors for increased periods of time, and indeed for their individual cancer cells, has lagged behind. Drugs are still tested in laboratory cell systems developed 40 years ago, which indicate a toxic effect of the antiandrogens on the tumor cells, not matched by direct studies of human tissues. In this review, I discuss the limits of our understanding of both how these drugs work and potential side effects, which are often overlooked in the face of a perceived urgency to get better inhibitors in to the clinic.Increasingly sophisticated therapies for chemical castration dominate first-line treatments for locally advanced prostate cancer. However, androgen deprivation therapy (ADT) offers little prospect of a cure, as resistant tumors emerge rather rapidly, normally within 30 months. Cells have multiple mechanisms of resistance to even the most sophisticated drug regimes, and both tumor cell heterogeneity in prostate cancer and the multiple salvage pathways result in castration-resistant disease related genetically to the original hormone-naive cancer. The timing and mechanisms of cell death after ADT for prostate cancer are not well understood, and off-target effects after long-term ADT due to functional extra-prostatic expression of the androgen receptor protein are now increasingly being recorded. Our knowledge of how these widely used treatments fail at a biological level in patients is deficient. In this review, I will discuss whether there are pre-existing drug-resistant cells in a tumor mass, or whether resistance is induced/selected by the ADT. Equally, what is the cell of origin of this resistance, and does it differ from the treatment-naïve tumor cells by differentiation or dedifferentiation? Conflicting evidence also emerges from studies in the range of biological systems and species employed to answer this key question. It is only by improving our understanding of this aspect of treatment and not simply devising another new means of androgen inhibition that we can improve patient outcomes.

Roles of NANOGP8 in cancer metastasis and cancer stem cell invasion during development of castration-resistant prostate cancer.

BackgroundProstate cancer (PCa) is one of the most common types of cancer and the emerging resistance to androgen deprivation therapy in PCa aggravates disease progression. In this study, we examined the potential pro-tumorigenic functions of NANOGP8 in prostate cancer development.MethodsQuantitative RT-PCR confirmed higher NANOGP8 expression in androgen independent tumors, as well as a recurrent prostate tumor in patient samples. We then established a novel two-way inducible NANOGP8-short hairpin RNA experimental system, in which the NANOGP8 expression was transiently induced by adding doxycycline in the diet of NOD/SCID mice.ResultsThe knockdown of NANOGP8 inhibited implanted tumor growth and the progression of castration-resistant PCa. NANOGP8-deficient PCa cells lost their cancer stem cell and gene expression programs. To further investigate the functions of NANOGP8 in PCa stem cells, real-time cell tracking was used to monitor the cell division modes and differentiation patterns of NANOGP8+ cells. The expression level of NANOGP8 markedly influenced the cell division mode of NANOGP8+ PCa cells and was strongly correlated with their pluripotency, reflected by robust telomerase activity and longer telomere length. NANOGP8 expression was also associated with the metastatic capacity of PCa cells.ConclusionsBased on these findings, we propose that NANOGP8 could serve as an effective therapeutic target for the treatment of PCa.

Systemic inflammation and symptomatology in patients with prostate cancer treated with androgen deprivation therapy: Preliminary findings.

Increases in fatigue, depressive symptomatology, and cognitive impairment are common after the initiation of androgen deprivation therapy (ADT) for prostate cancer. To date, no studies have examined the potential role of inflammation in the development of these symptoms in ADT recipients. The goal of the current study was to examine circulating markers of inflammation as potential mediators of change in fatigue, depressive symptomatology, and cognitive impairment related to the receipt of ADT. Patients treated with ADT for prostate cancer (ADT+; n = 47) were assessed around the time of the initiation of ADT and 6 and 12 months later. An age- and education-matched group of men without a history of cancer (CA-; n = 82) was assessed at comparable time points. Fatigue, depressive symptomatology, and cognitive impairment were assessed with the Fatigue Symptom Inventory, the Center for Epidemiological Studies Depression Scale, and a battery of neuropsychological tests, respectively. Circulating markers of inflammation included interleukin 1 receptor antagonist (IL-1RA), interleukin 6 (IL-6), soluble tumor necrosis factor receptor II (sTNF-RII), and C-reactive protein (CRP). Fatigue, depressive symptomatology, and serum IL-6 increased significantly over time in the ADT+ group versus the CA- group; rates of cognitive impairment also changed significantly between the groups. No significant changes in IL-1RA, sTNF-RII, or CRP over time were detected. Treatment-related increases in IL-6 were associated with worsening fatigue but not depressive symptomatology or cognitive impairment. Results of this preliminary study suggest that increases in circulating IL-6, perhaps due to testosterone inhibition, may play a role in fatigue secondary to receipt of ADT. Additional research is needed to determine whether interventions to reduce circulating inflammation improve fatigue in this population.

HSD3B1 variant and androgen-deprivation therapy outcome in prostate cancer.

Rate-limiting enzyme 3b-hydroxysteroid dehydrogenase type 1 (3βHSD1) encoded by HSD3B1 catalyzes the transition of dehydroepiandrosterone (DHEA) to dihydrotestosterone (DHT). The HSD3B1 (1245C) variant renders 3bHSD1 of resistant to ubiquitination and degradation, leading to a large amount of protein accumulation in the cell. Multiple clinical studies have shown that this mutation was correlated with resistance to androgen-deprivation therapy in prostate cancer. However, the results were not consistent depending on different treatment strategy and in some researches, the number of observed cases was relatively small. To determine the effects of HSD3B1 (1245C) variant on resistance to androgen-deprivation therapy in prostate cancer, we performed a meta-analysis of the available literature. Electronic database searches identified appropriately designed studies that detected HSD3B1 in prostate cancer. We conducted a systematic search of studies in the following databases: PubMed, and EMBASE published until August 10, 2020 using the following search terms: (HSD3B1 AND ((((prostate cancer) OR prostatic neoplasm) OR prostatic carcinoma) OR prostatic cancer). Eight researches were included in this research. The result validated that the HSD3B1 (1245C) variant allele was associated with a shorter PFS (HR, 1.97; 95% CI, 1.39-2.79; P = 0.0001) (homozygous wild-type group) in men with prostate cancer when treated with ADT, however, a higher PFS (HR, 0.68; 95% CI, 0.48-0.96; P = 0.03) when treated with ADT and CYP17A1 inhibitor. The HSD3B1 (1245C) variant is a predictor of ADT plus CYP17A1 inhibitor response in prostate cancer.