Although Androgen Deprivation Therapy Research Articles

Abstract CT137: Efficacy and immunological outcomes of non-fucosylated anti-CTLA-4 (BMS-986218) + degarelix acetate vs. degarelix acetate alone in men with high-risk localized prostate cancer (Neo-Red-P)

Abstract Background: Men with high-risk localized prostate cancer are at significant risk for disease recurrence and there is currently no role for neoadjuvant therapy. Although androgen deprivation therapy (ADT) is immunomodulatory and can increase CD8 T cell infiltration, these effects are counterbalanced by the expansion of suppressive regulatory T cells (Tregs). We therefore designed a correlative-rich clinical trial for men with high-risk localized prostate cancer to test whether BMS-986218 - a novel afucosylated anti-CTLA-4 antibody optimized for antibody-dependent cell-mediated cytotoxicity (ADCC) - depletes Tregs and augments response to ADT. Methods: Neo-Red-P is a single-center, two-arm, open-label pilot study assessing degarelix (ADT) versus ADT + anti-CTLA-4-NF (BMS-986218) in patients with treatment naïve high-risk localized prostate cancer. Key eligibility criteria included histologically confirmed adenocarcinoma with Gleason sum of ≥4+3 and clinical stage T1c-T3bN0M0. All patients received degarelix (ADT; 240mg SQ) 2 weeks before radical prostatectomy (RP). Patients were randomized to Arm A (ADT only), or Arm B (ADT + BMS-986218 [20mg IV] 2 doses Q2w starting 3 weeks before RP). The primary endpoint was the safety and feasibility of neoadjuvant BMS-986218 in prostate cancer. Secondary endpoints included the pathologic complete response rate, rate of undetectable PSA at 12 months, PSA response rate (>50% decrease pre-RP), and time-to-PSA recurrence. Fresh tumor specimens were collected at RP for single-cell RNA-sequencing, cytometry by time-of-flight, next-generation sequencing, and multiplex immunofluorescence. A treatment naïve cohort of matching demographic and pathological characteristics was collected for comparative analysis (n=14). Results: Between February 26, 2020, and November 15, 2022, 24 patients were enrolled. Severe treatment-related adverse events (TRAE; Grade ≥ 3) were rare in both arms; 0% in the ADT alone arm and 4% in the combination arm, suggesting a tolerable safety profile with the addition of BMS-986218. In the combination arm, 54% of subjects achieved a 50% reduction in PSA versus 33% in the ADT alone arm. In the ADT alone arm, 80% of patients had an undetectable PSA at 12 months, with a median recurrence-free survival of 1.61 years (IQR: 1.50-1.99 years). In the combination group, 75% had an undetectable PSA at 12 months, with a median recurrence-free survival of 1.82 years (IQR: 0.89-2.07 years). The overall recurrence rate in patients treated with combination therapy was 25% (3 of 12 patients) versus 20% (2 of 10 patients) in the ADT alone arm. Correlative studies suggest that aCTLA4-NF mitigates ADT-induced Treg accumulation through enhanced Fc receptor activity and augmented CTL activation, indicating an enhanced anti-tumor response with combination therapy. Conclusions: The neoadjuvant combination of ADT + aCTLA-4-NF (BMS-986218) is feasible, well tolerated, and induces significant remodeling of the immune TME through enhanced Fc receptor and CTL activity. Rates of disease recurrence following surgery were low in this high-risk population, warranting further investigation of combination immuno-hormonal therapy in the neoadjuvant setting for high-risk prostate cancer. Clinical Trial Information: NCT04301414 Citation Format: Patrick J. McCann, Casey R. Ager, Aleksandar Z. Obradovic, Matthew G. Chaimowitz, Samuel Pan, Caroline J. Laplaca, Parin Shah, Renu K. Virk, Christopher B. Anderson, Catherine S. Spina, Karie D. Runcie, Mark N. Stein, Charles G. Drake, Matthew C. Dallos. Efficacy and immunological outcomes of non-fucosylated anti-CTLA-4 (BMS-986218) + degarelix acetate vs. degarelix acetate alone in men with high-risk localized prostate cancer (Neo-Red-P) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT137.

Glycolysis related lncRNA SNHG3 / miR-139-5p / PKM2 axis promotes castration-resistant prostate cancer (CRPC) development and enzalutamide resistance

Although androgen deprivation therapy (ADT) by the anti-androgen drug enzalutamide (Enz) may improve the survival level of patients with castration-resistant prostate cancer (CRPC), most patients may eventually fail due to the acquired resistance. The reprogramming of glucose metabolism is one type of the paramount hallmarks of cancers. PKM2 (Pyruvate kinase isozyme typeM2) is a speed-limiting enzyme in the glycolytic mechanism, and has high expression in a variety of cancers. Emerging evidence has unveiled that microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have impact on tumor development and therapeutic efficacy by regulating PKM2 expression. Herein, we found that lncRNA SNHG3, a highly expressed lncRNA in CRPC via bioinformatics analysis, promoted the invasive ability and the Enz resistance of the PCa cells. KEGG pathway enrichment analysis indicated that glucose metabolic process was tightly correlated with lncRNA SNHG3 level, suggesting lncRNA SNHG3 may affect glucose metabolism. Indeed, glucose uptake and lactate content determinations confirmed that lncRNA SNHG3 promoted the process of glycolysis. Mechanistic dissection demonstrated that lncRNA SNHG3 facilitated the advance of CRPC by adjusting the expression of PKM2. Further explorations unraveled the role of lncRNA SNHG3 as a ‘sponge’ of miR-139-5p and released its binding with PKM2 mRNA, leading to PKM2 up-regulation. Together, Our studies suggest that lncRNA SNHG3 / miR-139-5p / PKM2 pathway promotes the development of CRPC via regulating glycolysis process and provides valuable insight into a novel therapeutic approach for the disordered disease.

Personalizing approaches to the management of metastatic hormone sensitive prostate cancer: role of advanced imaging, genetics and therapeutics.

To summarize contemporary and emerging strategies for the diagnosis and management of metastatic hormone sensitive prostate cancer (mHSPC), focusing on diagnostic testing and therapeutics. Literature review using PUBMED-Medline databases as well as clinicaltrials.gov to include reported or ongoing clinical trials on treatment for mHSPC. We prioritized the findings from phase III randomized clinical trials, systematic reviews, meta-analyses and clinical practice guidelines. There have been significant changes to the diagnosis and staging evaluation of mHSPC with the integration of increasingly accurate positron emission tomography (PET) imaging tracers that exceed the performance of conventional computerized tomography (CT) and bone scan. Germline multigene testing is recommended for the evaluation of patients newly diagnosed with mHSPC given the prevalence of actionable alterations that may create candidacy for specific therapies. Although androgen deprivation therapy (ADT) remains the backbone of treatment for mHSPC, approaches to first-line treatment include the integration of multiple agents including androgen receptor synthesis inhibitors (ARSI; abiraterone) Androgen Receptor antagonists (enzalutamide, darolutamide, apalautamide), and docetaxel chemotherapy. The combination of ADT, ARSI, and docetaxel chemotherapy has recently been evaluated in a randomized trial and was associated with significantly improved overall survival including in patients with a high burden of disease. The role of local treatment to the prostate with radiation has been evaluated in randomized trials with additional studies underway evaluating the role of cytoreductive radical prostatectomy. The staging and initial management of patients with mHSPC has undergone significant advances in the last decade with advancements in the diagnosis, treatment and sequencing of therapies.

Abstract 4975: Anti-cancer effect of a probiotic bacteria-derived compound, 1,4-Dihydroxy-2-naphthoic acid in prostate cancer

Abstract Cancer incidence has been increasing globally and the major cause for mortality associated with this disease is due to metastasis development. Followed by skin and lung cancer, prostate cancer (PCa) is one of the most common cancers prevailing among older men in the United States. Although androgen deprivation therapy (ADT) is the mainstay treatment for PCa, most patients undergoing ADT eventually develop metastatic PCa. Moreover, other treatment options, such as chemotherapy and radiotherapy, have toxic side effects and are ineffective in controlling advanced PCa. Hence, there arises a need for identifying alternative agents with possibly fewer side effects. The gut biome plays a significant role in regulating many bodily functions like digestion, immunity, and including cancer prevention. Probiotics, commonly known as 'good bacteria,' are living microorganisms that provide health promoting benefits. A probiotic metabolite, 1,4-Dihydroxy-2-naphthoic acid (DHNA), is an anti-inflammatory aryl hydrocarbon receptor (Ahr) agonist which is yet to be explored for its anticancer activity. Inhibiting the inflammatory signaling axis and activating Ahr by DHNA could be a promising strategy to counteract metastatic PCa. Cell viability assays revealed that 1,4-DHNA is highly toxic in metastatic prostate cancer cell lines such as DU145 and PC3 compared to normal prostate epithelial cells like RWPE-1 and human prostate stromal myofibroblast cell line, WPMY-1, with an approximate IC50 value of 5 µM in DU145 and PC3 and about 20 µM and 75 µM in WPMY-1 and RWPE-1 respectively. DHNA reduced the colony forming abilities of BPH-Cd, PC3, and DU145 in clonogenic assay and suppressed the BPH-Cd spheroid growth in spheroid formation assay, revealing its anti-tumorigenic potential. Trans-well migration assay using BPH-Cd, PC3, and DU145 showed a decrease in cell migration, hinting at the drug's anti-metastatic ability. G2/M phase arrest in cell cycle analysis and dose-dependent increase in apoptosis of DHNA-treated DU145, PC3, and LNCaP cell lines reiterated its anti-cancer potential. Western blot results in PC3 and DU145 showed significant dose-dependent inhibition of protooncogene β-catenin expression. Downregulation of cell cycle proteins like cyclin D1 and increased expression of effector caspase, cleaved caspase 7 support cell death promoting effects of DHNA via an intrinsic apoptotic pathway. Our pre-clinical data suggest that DHNA can be a potential drug for inhibiting both prostate tumor growth and metastasis. Further research is warranted to ascertain the anti-metastatic and underlying anti-cancer mechanisms to help translate the findings to clinical use. Citation Format: Shreeja Srinivas Bitla, Gnanasekar Munirathinam. Anti-cancer effect of a probiotic bacteria-derived compound, 1,4-Dihydroxy-2-naphthoic acid in 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 4975.

MP11-01 PRESCRIPTION PATTERNS OF SYSTEMIC THERAPY IN THE MANAGEMENT OF METASTATIC CASTRATION-SENSITIVE PROSTATE CANCER

You have accessJournal of UrologyCME1 Apr 2023MP11-01 PRESCRIPTION PATTERNS OF SYSTEMIC THERAPY IN THE MANAGEMENT OF METASTATIC CASTRATION-SENSITIVE PROSTATE CANCER Joseph Black, David Einstein, Xin Gao, Xiao Wei, Brendan Connell, Nick Kamkari, Boris Gershman, and Aria Olumi Joseph BlackJoseph Black More articles by this author , David EinsteinDavid Einstein More articles by this author , Xin GaoXin Gao More articles by this author , Xiao WeiXiao Wei More articles by this author , Brendan ConnellBrendan Connell More articles by this author , Nick KamkariNick Kamkari More articles by this author , Boris GershmanBoris Gershman More articles by this author , and Aria OlumiAria Olumi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003226.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Metastatic castration-sensitive prostate cancer (mCSPC) is an incurable disease. Although androgen deprivation therapy (ADT) remains the backbone treatment for patients with mCSPC, multiple randomized studies since 2015 have demonstrated that treatment intensification with the addition of taxanes and/or novel hormonal therapies (NHT) confers significantly improved overall survival. This adds complexity for providers with developing an individual therapeutic approach for patients with mCSPC. Provider prescription patterns for mCSPC are heterogenous, which may present barriers for patients in receiving newer interventions. To investigate this, we conducted a retrospective analysis on the prescription utilization patterns of clinicians initiating treatment for patients with mCSPC. METHODS: Pharmacy and claims data were queried from 2015-2022 to identify patients with prostate cancer (PCa). The dataset includes 18 million US cancer patients, including Medicaid, Medicare, Medicare Part D, and cash transactions. Patients with mCSPC were identified using at minimum two ICD9/10 diagnosis codes and/or medications on separate days. Drug classes analyzed include NHT, 1st-generation anti-androgens, chemotherapy, and LHRH monotherapy. Prescription rates of each class of drug were stratified by patient and provider baseline characteristics. RESULTS: NHT prescription has increased, while chemotherapy, first generation anti-androgens, and LHRH monotherapy have either remained unchanged or decreased since 2015. No variation in prescription patterns were observed between urban and rural settings. Medical oncologists were more likely to prescribe NHT than urologists (45% vs. 19%), whereas urologists were more likely to prescribe LHRH monotherapy (69% v 38%). CONCLUSIONS: Since 2015, NHT utilization and treatment intensification has nationally increased for mCSPC and prescription patterns do not vary between rural and urban settings. When compared to urologists, medical oncologists have more readily incorporated newer therapeutics for mCSPC and decreased the usage of LHRH monotherapy for patients with mCSPC. These data represent a potential area for growth for urologists in the treatment of mCSPC. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e123 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Joseph Black More articles by this author David Einstein More articles by this author Xin Gao More articles by this author Xiao Wei More articles by this author Brendan Connell More articles by this author Nick Kamkari More articles by this author Boris Gershman More articles by this author Aria Olumi More articles by this author Expand All Advertisement PDF downloadLoading ...

Clostridium scindens metabolites trigger prostate cancer progression through androgen receptor signaling.

Prostate cancer (PCa) is one of the most common malignancies in men; recently, PCa-related mortality has increased worldwide. Although androgen deprivation therapy (ADT) is the standard treatment for PCa, patients often develop aggressive castration-resistant PCa (CRPC), indicating the presence of an alternative source of androgen. Clostridium scindens is a member of the gut microbiota and can convert cortisol to 11β-hydroxyandrostenedione (11β-OHA), which is a potent androgen precursor. However, the effect of C. scindens on PCa progression has not been determined. In this study, androgen-dependent PCa cells (LNCaP) were employed to investigate whether C. scindens-derived metabolites activate androgen receptor (AR), which is a pivotal step in the development of PCa. Results showed that cortisol metabolites derived from C. scindens-conditioned medium promoted proliferation and enhanced migration of PCa cells. Furthermore, cells treated with these metabolites presented activated AR and stimulated AR-regulated genes. These findings reveal that C. scindens has the potential to promote PCa progression via the activation of AR signaling. Further studies on the gut-prostate axis may help unravel an alternative source of androgen that triggers CRPC exacerbation.

Androgen deprivation therapy plus chemotherapy ± androgen receptor-targeting agents for metastatic hormone-sensitive prostate cancer

Although androgen deprivation therapy (ADT) alone has been the standard of care (SOC) in the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) for decades, combination therapies of novel hormone therapy (androgen receptor-targeting agents [ARTA]) or docetaxel chemotherapy have more recently replaced single ADT treatment. In addition, data for triplet therapies with ADT plus ARTA (abiraterone/darolutamide) and docetaxel chemotherapy are now available. The present review addresses the question which therapy is suitable for which mHSPC patient. Who benefits from doublet therapy and which patient from triplet therapy? Which side effects can be expected? Triplet therapy consisting of ADT + docetaxel + abiraterone/darolutamide resulted in asignificantly longer overall survival compared to therapy consisting of ADT + docetaxel of all mHSPC (ARASENS) and primary metastatic high-volume (PEACE-1) mHSPC patients. In the setting of high-volume mHSPC, prolonged overall survival is seen for the specific triplet combination of ADT + docetaxel + abiraterone. In the low-volume mHSPC setting, only an extended progression-free survival but not overall survival was observed. Data regarding the classification of high- vs. low-volume mHSPC for the triplet therapy consisting of darolutamide are currently not available. Side effects with triplet therapies are almost comparable with those of doublet therapies and relate to typical chemotherapy-associated (neutropenia) and ARTA-specific side effects (abiraterone). ADT alone or ADT + docetaxel should no longer play arole in first-line therapy for mHSPC. Accordingly, therapy consisting of ADT + ARTA or ADT + ARTA + docetaxel represents the current primary treatment option pending further data and regarding patient-specific characteristics (age, ECOG status, metastatic burden, primary/secondary metastatic disease).

Association of Gonadotropin-Releasing Hormone Therapies With Venous Thromboembolic Events in Patients With Prostate Cancer: A National Cohort Study.

Although androgen deprivation therapy (ADT) has been proposed to be associated with a higher risk of venous thromboembolisms (VTEs), whether gonadotropin-releasing hormones (GnRHs), such as both agonists and antagonists, are also associated with VTEs remain unclear. Using the Taiwan Cancer Registry (TCR) linked with the National Health Insurance Research Database, we identified patients diagnosed with prostate cancer from 2008 to 2015. Patients who received GnRH were 1:1 propensity score matched with non-GnRH users by age and cancer stage at diagnosis and clinical stage. Cox regression analysis was applied to estimate the incidences of VTEs with death as a competing event at the 5-year follow-up. The VTE incidence among GnRH users was 1.13% compared with 0.98% among non-users. After adjusting with potential confounding factors, the risk of VTEs showed borderline statistical significance among GnRH users and non-users. Notably, in the subgroup analysis among patients receiving GnRH therapy, those younger than 70 years old or at an earlier stage (stage I/II) were at a higher risk of VTEs. Different from previous studies, our findings highlighted critical concerns regarding the cardiac safety of GnRH therapies in prostate cancer patients at a relatively younger age or at an earlier stage.

Androgen Receptor-Dependent Mechanisms Mediating Drug Resistance in Prostate Cancer.

Simple SummaryProstate cancer can develop under hormone treatment and chemotherapy from a castration-sensitive towards a castration-resistant into a drug resistant-tumor. The main hormonal drug target is the androgen receptor (AR). Androgen deprivation therapy reduces body-own androgen production and AR antagonists inhibit androgen-mediated activation of AR. Here, molecular mechanisms are described that review knowledge about tumor cells escape therapy by developing bypass mechanisms of AR-signaling. This includes genomic and non-genomic signaling. Deciphering the involved molecules that mediate castration and drug resistance will provide the basis of potential novel drug targets that may be used in addition to AR inhibition as combinatory treatment.Androgen receptor (AR) is a main driver of prostate cancer (PCa) growth and progression as well as the key drug target. Appropriate PCa treatments differ depending on the stage of cancer at diagnosis. Although androgen deprivation therapy (ADT) of PCa is initially effective, eventually tumors develop resistance to the drug within 2–3 years of treatment onset leading to castration resistant PCa (CRPC). Castration resistance is usually mediated by reactivation of AR signaling. Eventually, PCa develops additional resistance towards treatment with AR antagonists that occur regularly, also mostly due to bypass mechanisms that activate AR signaling. This tumor evolution with selection upon therapy is presumably based on a high degree of tumor heterogenicity and plasticity that allows PCa cells to proliferate and develop adaptive signaling to the treatment and evolve pathways in therapy resistance, including resistance to chemotherapy. The therapy-resistant PCa phenotype is associated with more aggressiveness and increased metastatic ability. By far, drug resistance remains a major cause of PCa treatment failure and lethality. In this review, various acquired and intrinsic mechanisms that are AR‑dependent and contribute to PCa drug resistance will be discussed.

UpFrontPSMA: A randomized phase II study of sequential 177Lu-PSMA617 and docetaxel versus docetaxel in metastatic hormone-naïve prostate cancer (mHNPC).

TPS180 Background: 177Lu‐PSMA-617 (Lu-PSMA) is a radiolabeled small-molecule that binds with high affinity to PSMA enabling highly targeted delivery of beta radiation to prostate cancer cells. In metastatic castration-resistant prostate cancer, Lu-PSMA showed superior activity to Cabazitaxel in the TheraP trial. Although androgen deprivation therapy (ADT) + Docetaxel is a standard of care for de novo high-volume mHNPC, outcomes remain sub-optimal for many patients. We hypothesize that Lu-PSMA prior to docetaxel will achieve a higher undetectable PSA rate at 12 months compared to docetaxel alone in men with newly-diagnosed high-volume mHNPC. Methods: UpFrontPSMA is an open label, randomized, stratified, 2-arm, multi-center, phase 2 clinical trial recruiting 140 patients at 11 Australian centers. Key eligibility criteria include histological diagnosis of prostate cancer within 12 weeks, PSA > 10ng/ml at diagnosis, < 4 weeks on ADT, and high-volume (≥ 4 bone metastases with ≥ 1 outside the axial skeleton, and/or visceral metastases), PSMA-avid disease on 68Ga-PSMA-11 PET/CT with no major discordance on 18FDG-PET/CT. Patients will be randomized 1:1 to the experimental arm (Lu-PSMA 7.5 GBq q6w x 2 cycles followed 6 weeks later by docetaxel 75mg/m2 q3w x 6 cycles), or standard-of-care Arm (docetaxel alone). All patients will receive continuous ADT. Assessments will be done every 3 weeks during study treatment, and then every 6-12 weeks until unequivocal disease progression. CT and whole body bone scan will be performed at baseline and every 12 weeks, 68Ga-PSMA-11 PET/CT at baseline and 12 weeks, and 18FDG-PET/CT at baseline and 12 weeks (if applicable). Correlative samples will include optional tumour tissue (baseline and disease progression), and serial plasma/whole blood collection. The primary endpoint is undetectable PSA (≤ 0.2 ng/ml) at 12 months. Secondary endpoints are safety, time to castration resistance, PSA-progression-free-survival (PSA-PFS), radiographic PFS, radiographic response rates, early PSMA-PET response rates, quality of life and overall survival. Exploratory endpoints are prognostic and predictive value of PET-derived parameters and of biomarkers identified in plasma/whole blood/tumour tissue. The study will have 85% power to reject the null hypothesis if the true 12 month undetectable PSA rate in the experimental Arm is 50%. The power calculation assumes no more than 10 patients (7%) of the 140 patients will be unevaluable or lost to follow-up in 1 year, 5% alpha and two-sided test for proportions. As of October 13, 2020, accrual stands at 4. UpFrontPSMA is an investigator-led, academic trial sponsored by Peter MacCallum Cancer Centre in collaboration with ANZUP Cancer Trials Group with study coordination provided by the Centre for Biostatistics and Clinical Trials (BaCT) Clinical trial information: NCT04343885.

New treatments for patients with non‐metastatic castration‐resistant prostate cancer: A nursing perspective

AbstractGlobally, prostate cancer (PC) is a leading cause of death in men. Although androgen deprivation therapy (ADT) is the cornerstone of treatment for the disease, most patients eventually develop castration‐resistant PC (CRPC). Patients with non‐metastatic (nm) CRPC, the earliest clinical manifestation of castration resistance, are at risk of progressing to metastatic CRPC, which is associated with reduced life expectancy and poor quality of life. The nmCRPC treatment landscape has recently been transformed by the approval of three next‐generation oral androgen receptor (AR) inhibitors: apalutamide, enzalutamide and darolutamide. This review addresses available new treatment options for nmCRPC that target the AR, considering the effects of adverse event (AE) profiles and drug‐drug interactions (DDIs) when tailoring patient‐centric treatment to individual need, and discussing management strategies and nursing interventions for patients who experience drug‐related AEs. While no head‐to‐head comparisons of apalutamide, enzalutamide and darolutamide have been conducted to date, all three drugs have demonstrated comparable efficacy and maintained quality of life in phase III clinical trials, with differing AE profiles. The three treatments also demonstrate different potential for DDIs with other common medications that may be taken simultaneously. With the availability of new AR‐targeted options for nmCRPC, oncology nurses play a crucial role in the decision‐making process, educating and supporting patients on managing their PC, and ensuring that they receive the most appropriate treatment. As patients with nmCRPC are largely asymptomatic from their disease (with the exception of urinary/erectile symptoms), maintaining quality of life becomes a major objective when prescribing pharmacotherapy. Therefore, weighing treatment efficacy against the respective drug safety profile and examining the potential for adverse drug interactions with concomitant medications are important clinical considerations. Oncology nurses educate patients on potential treatment‐emergent AEs and their management and serve as advocates to ensure that patients receive optimal care based on their individual therapeutic requirements. They also provide information on available auxiliary services for patients and caregivers. This article provides an overview for the oncology nurse of the efficacy, safety, quality of life and DDI potential of these new AR‐targeted therapies in the nmCRPC setting, highlighting considerations for tailoring patient‐centric treatment to individual need. The importance of the oncology nurse in managing adverse drug reactions associated with ADT and AR inhibitors is highlighted and recommendations provided.

Cancer-driven IgG promotes the development of prostate cancer though the SOX2-CIgG pathway.

Although androgen deprivation therapy (ADT) is the initial treatment strategy for prostate cancer (PCa), recurrent castration-resistant prostate cancer (CRPC) eventually ensues. In this study, cancer-derived immunoglobulin G (CIgG) is found to be induced after ADT, identifying CIgG as a potential CRPC driver gene. The expression of CIgG and its clinical significance in PCa tissue was analyzed by The Cancer Genome Atlas database and immunohistochemistry. Subsequently, the sequence features of prostate cell line VHDJH rearrangements were analyzed. We also assessed the effect of CIgG on the migratory, invasive and proliferative abilities of PCa cells in vitro and vivo. Suspended microsphere, colony formation and drug-resistant assays were performed using PC3 cells with high CIgG expression (CIgGhigh ) and low CIgG expression (CIgG-/low ), and A nonobese diabetic/severe combined immunodeficiency mouse tumor xenograft model was developed for the study of the tumorigenic effects of the different cell populations. The SOX2-CIgG signaling pathway was validated by immunohistochemistry, immunofluorescence, quantitative reverse transcription-polymerase chain reaction, Western blot, luciferase, and chromatin immunoprecipitation assays and bioinformatics analyses. Finally, we investigated the effect of RP215 inhibition on the progression of PCa in vivo using a Babl/c nude mouse xenograft model. CIgG is frequently expressed in PCa and associated with clinicopathological characteristics, moreover, CIgG transcripts with unique patterns of VHDJH rearrangements are found in PCa cells. Functional analyses identified that CIgG was induced by ADT and upregulated by SOX2 (SRY (sex determining region Y)-box 2) in PCa, promoting the development of PCa. In addition, our findings underscore a novel role of CIgG signaling in the maintenance of stemness and the progression of cancer through mitogen activated protein kinase/extracellular-signal-regulated kinase and AKT in PCa. In vivo experiments further demonstrated that depleting CIgG significantly suppressed the growth of PCa cell xenografts. Furthermore, a CIgG monoclonal antibody named RP215 exhibits tumor inhibitory effect as well. Our data suggests that CIgG could be a driver of PCa development, and that targeting the SOX2-CIgG axis may therefore inhibit PCa development after ADT.

Effects Of Exercise On Disablement Process Outcomes In Prostate Cancer Patients Undergoing Androgen Deprivation Therapy: An Updated Systematic Review

Although androgen-deprivation therapy (ADT) is a foundation of treatment for prostate cancer (PCa) patients, adverse effects of ADT may accelerate functional decline. Whereas exercise improves muscular strength and functional performance in PCa patients, evidence of the benefits of exercise for alternative disablement process outcomes remain equivocal. PURPOSE: To update the findings of our previous systematic review of the effects of exercise on disablement process outcomes in PCa patients undergoing ADT. The purpose of this study is to determine the extent to which exercise interventions produce meaningful improvements in the specific impairment domain outcome of body composition (BC) in PCa patients on ADT. METHODS: A comprehensive literature search was conducted of all relevant published studies from December 2013-present. Data were extracted on BC outcomes from 8 published exercise intervention studies involving 307 PCa patients on ADT. The magnitude of pre- to post-intervention change was examined. To isolate the effects of exercise, studies combining other interventions were excluded. Weighted, bias-corrected Cohen’s d effect sizes were calculated for change in each outcome and averaged across included studies. RESULTS: Results revealed that exercise yielded small average improvements in lean body mass (d = 0.09), appendicular lean mass (d = 0.08), trunk fat mass (d = -0.03) and visceral fat mass (d = -0.11). All other measures of whole-body and regional BC showed negligible average effects of exercise. CONCLUSIONS: The findings of this updated systematic review suggest that while exercise attenuates the established adverse effects of ADT on BC, the magnitude of exercise-induced improvements in BC outcomes is small and inconsistent across studies. These findings have important implications for delineating the effect of exercise on disablement process outcomes and underscore the potential utility of complementing exercise with targeted nutritional approaches in the supportive care of PCa patients on ADT.

Trends and oncological outcome of testosterone recovery after androgen deprivation therapy in prostate cancer patients who received external beam radiotherapy.

345 Background: Although androgen deprivation therapy (ADT) combined with external beam radiation therapy (EBRT) is standard treatment for high risk prostate cancer (PC) patients, the shift of testosterone (TST) levels after ADT and the optimal duration of ADT is unclear. TST recovery and outcome were studied in PC patients who received EBRT with ADT. Methods: Eighty-two patients who underwent EBRT with ADT for PC were retrospectively analyzed. Serum TST levels after ADT terminations were studied. Cox proportional hazard models and the Kaplan-Meier method were used for statistical analysis. Results: Median age, baseline TST, nadir TST, and duration of ADT were 73 years, 456 ng/dL, 16 ng/dL, and 26 months, respectively. ADT duration of 33 months (HR 0.13; p=0.0018), nadir TST of 20 ng/dL (HR 0.35; p=0.0112), and TST >50 ng/dL at 6 months after ADT termination (HR 0.21; p=0.0075) were significantly associated with TST recovery to normal levels (200 ng/dL) on multivariate analysis. ADT duration of 33 months (HR 0.31; p=0.0023) and nadir TST of 20 ng/dL (HR 0.38; p=0.0012) were significantly associated with TST recovery to supracastrate level (50 ng/dL) on multivariate analysis. In high risk PC patients, ADT≤ 2 year group showed shorter time to TST recovery to supracastrate levels compare to those of ADT>2 year group (HR 4.21; p=0.0022) without affecting biochemical recurrence (p=0.49) and overall survival (p=0.674). Conclusions: ADT duration of 33 months and nadir TST of 20 ng/dL predicted the TST recovery to suparacastrate levels. Less than 2 year of ADT provided better TST recovery without affecting the oncological outcome in high risk patients.[Table: see text]

Dihydrotestosterone Increases Cytotoxic Activity of Macrophages on Prostate Cancer Cells via TRAIL.

Although androgen deprivation therapy (ADT) and immunotherapy are potential treatment options in men with metastatic prostate cancer (CaP), androgen has conventionally been proposed to be a suppressor of the immune response. However, we herein report that DHT activates macrophages. When the murine macrophage cell line (RAW 264.7), human monocyte cell line (THP-1), and human peripheral blood monocytes were cultured with androgen-resistant CaP cell lines, DHT increased cytotoxicity of macrophages in a concentration-dependent manner. Further studies revealed that DHT induced M1 polarization and increased the expression levels of TNF-related apoptosis-inducing ligand (TRAIL) in macrophages and that this effect was abrogated when TRAIL was neutralized with a blocking antibody or small interfering RNA. Subsequent experiments demonstrated that induction of TRAIL expression was regulated by direct binding of androgen receptor to the TRAIL promoter region. Finally, an in vivo mouse study demonstrated that castration enhanced the growth of an androgen-resistant murine CaP tumor and that this protumorigenic effect of castration was blocked when macrophages were removed with clodronate liposomes. Collectively, these results demonstrate that DHT activates the cytotoxic activity of macrophages and suggest that immunotherapy may not be optimal when combined with ADT in CaP.

A phase II study of nivolumab in patients with high-risk biochemically recurrent (BCR) prostate cancer (PCa).

TPS341 Background: Although androgen deprivation therapy (ADT) may be used for high-risk BCR PCa prior to radiographic metastases, evidence is lacking and toxicities are clear. Recent data show higher prevalence of programmed death-ligand 1 (PD-L1) expression in primary PCa than previously seen. Tumor PD-L1 expression also significantly correlates with risk of BCR, suggesting that inhibition of innate immune function could be associated with recurrence. Finally, immune-suppressive immune cells may increase after castration resistance, so the early-stage tumor microenvironment may differ from the castration-resistant setting in which prior studies were conducted. These data justify a novel trial investigating PD-1 inhibition in the setting of BCR. We hypothesize that PD-L1 expression in primary PCa is a marker of immunogenicity and therefore may predict for response to PD-1 inhibition. Methods: We designed a single-arm phase 2 clinical trial of nivolumab 480 mg every 28 days for men experiencing high-risk BCR. The primary endpoint is the proportion of patients experiencing PSA decline or stabilization (without symptomatic/radiographic progression) after 12 weeks of nivolumab; secondary endpoints are best PSA response, change in PSA doubling time, time to ADT initiation and to metastatic disease, and safety. The study will include one cohort with PD-L1 expression on tumor cells >5% (“PD-L1-positive”), the other, PD-L1-negative, thus enriched for but not limited to PD-L1-expressing primary PCa. We are conducting correlative studies using tumor tissue and blood samples collected during treatment. We will perform next-generation sequencing on tissue to identify genomic biomarkers correlated with PD-L1 expression and with response to nivolumab. Using neoantigen prediction models, we will examine whether there are peripheral T cells present in nivolumab responders that recognize tumor-associated neoantigens and are expanded by PD-1 inhibition. We will evaluate subsets of tumor-infiltrating lymphocytes, including “exhausted” phenotypes, and other infiltrating immune cells. Finally, we will assess changes in peripheral immune cells and plasma cytokines as potential biomarkers. Clinical trial information: NCT03637543.

Metastatic Castration-Sensitive Prostate Cancer: Optimizing Patient Selection and Treatment.

The treatment landscape for metastatic castration-sensitive prostate cancer (mCSPC) has rapidly evolved over the past 5 years. Although androgen-deprivation therapy (ADT) is still the backbone of treatment, the addition of docetaxel or abiraterone acetate has improved outcomes for patients with mCSPC and become standard of care. With multiple treatment options available for patients with mCSPC, treatment selection to optimize patient outcomes has become increasingly difficult. Here, we review the clinical trials involving ADT plus docetaxel or abiraterone and provide clinicians with guidelines for treatment. Although surgery and/or radiation are standard of care for localized, intermediate- and high-risk prostate cancer, these treatments are not routinely used as part of initial treatment plans for patients with de novo mCSPC. Recent clinical data are challenging that dogma, and we review the literature on the addition of surgery and radiation to systemic therapy for mCSPC. Finally, the standard of care for oligometastatic prostate cancer (a subset of mCSPC with limited metastases) has not been established compared with that for some other cancers. We discuss the recent studies on metastasis-directed therapy for treatment of oligometastatic prostate cancer.

Pharmacological inhibition of the Notch pathway enhances the efficacy of androgen deprivation therapy for prostate cancer.

Although androgen deprivation therapy (ADT) is a standard treatment for metastatic prostate cancer, this disease inevitably recurs and progresses to ADT-resistant stage after this therapy. Accordingly, understanding the mechanism of resistance to ADT and finding new approach to enhance the efficacy of ADT may provide a major benefit to PCa patients. In our study, we found upregulated expression of Notch receptors is positive associated with ADT-resistance progression. Using fluorescent Notch signaling reporter system, we observed that endogenous Notch signaling could be activated after treatment of androgen deprivation in LNCaP cells via activation of Notch3. In addition, exogenous activation of the Notch signaling though Dox-induced overexpression of any Notch intracellular domains (NICD1-4) could enhance the resistance of PCa cells to ADT under ex vivo 3D culture conditions and upregulate expression of ADT resistance-associated phospho-p38 and Bcl-2 in LNCaP cells. As a result, pharmacological inhibition of the Notch pathway using γ-secretase inhibitor (GSI), DAPT, downregulated both phospho-p38 and Bcl-2 expression and significantly enhanced the efficacy of ADT in androgen sensitive PCa cells with impaired proliferation and 3D colony formation, increased apoptosis and remarkable inhibition of tumor growth in murine subcutaneous xenograft model. These results indicate that activated Notch signaling contributes to ADT resistance, and suggest that inhibition of the Notch pathway may be a promising adjuvant therapy of ADT for PCa.

Effects of a Group-Mediated Exercise and Dietary Intervention in the Treatment of Prostate Cancer Patients Undergoing Androgen Deprivation Therapy: Results From the IDEA-P Trial.

Although androgen-deprivation therapy (ADT) is the foundation of treatment for prostate cancer, the physiological impacts of ADT result in functional decline and enhanced risk of chronic disease and metabolic syndrome. The Individualized Diet and Exercise Adherence Pilot Trial (IDEA-P) is a single-blind, randomized, pilot trial comparing the effects of a group-mediated, cognitive-behavioral (GMCB) exercise and dietary intervention (EX+D) with those of a standard-of-care (SC) control during the treatment of prostate cancer patients undergoing ADT. A total of 32 prostate cancer patients (M age = 66.28, SD = 7.79) undergoing ADT were randomly assigned to the 12-week EX+D intervention (n = 16) or control (n = 16). The primary outcome in IDEA-P was change in mobility performance with secondary outcomes including body composition and muscular strength. Blinded assessment of outcomes were obtained at baseline and at 2- and 3-month follow-ups. Favorable adherence and retention rates were observed, and no serious intervention-related adverse events were documented. Intent-to-treat ANCOVA controlling for baseline value and ADT duration demonstrated that EX+D resulted in significantly greater improvements in mobility performance (p < .02), muscular strength (p < .01), body fat percentage (p < .05), and fat mass (p < .03) at 3-month follow-up, relative to control. Findings from the IDEA-P trial suggest that a GMCB-based EX+D intervention resulted in significant, clinically meaningful improvements in mobility performance, muscular strength, and body composition, relative to controls. Collectively, these results suggest that the EX+D was a safe and well-tolerated intervention for prostate cancer patients on ADT. The utility of implementing this approach in the treatment of prostate cancer patients on ADT should be evaluated in future large-scale efficacy trials. NCT02050906.

The Economic Burden of Metastatic Castration Resistant Prostate Cancer and Skeletal Related Events in Japanese University Hospitals

Objective:Although androgen deprivation therapy (ADT) has improved the survival and quality of life of patients with prostate cancer, resistance to treatment inevitably results in transition to a castration resistant state (CRPC) and, in advanced cases, bone metastasis, leading to skeletal related events (SRE). In order to understand the current burden on patients in Japan, there is a need to estimate the healthcare costs of CRPC treatment in current clinical practice.Methods:This retrospective observational cohort study utilized claims data from 13 national university hospitals through the Platform for Clinical Information Statistical Analysis database. Extracted data included the use of diagnostic tests, the frequency and cost of hospitalizations and outpatient visits, and medication costs, using values from the Healthcare Fee System and the National Health Insurance Drug Price List relative to each observed year.Results:Data were collected from 4001 patients with CRPC, 97% of whom had undergone ADT. Between 2005 and 2016, the mean annualized direct medical cost per patient was ¥739,147 (US$7060), of which 91% was related to medication, 4.8% to laboratory and imaging, 4.1% to radiotherapy, and 0.1% to surgery. A total of 771 (19%) of the 4001 CRPC patients experienced an SRE. Resource utilization was significantly higher (p<0.0001) in patients with SRE than in those without, with mean annualized medication costs per patient of ¥1,074,885 and ¥659,006, respectively, and ¥108,807 and ¥71,392, respectively, for laboratory and imaging. The occurrence of even one SRE led to a significant increase in costs and the use of analgesics, compared to the prior period.Conclusions:A diagnosis of CRPC is associated with considerable healthcare resource utilization and increased economic burden on patients, which are significantly higher in those with SREs. Treatments that can prevent or delay SREs may help ease this burden, thereby providing cost savings across Japanese healthcare systems.