Androgen Deprivation Therapy Therapy Research Articles

Prevalence and risk evaluation of cardiovascular disease in the newly diagnosed prostate cancer population in China: A nationwide, multi-center, population-based cross-sectional study.

Cardiovascular disease (CVD) has emerged as the leading cause of death from prostate cancer (PCa) in recent decades, bringing a great disease burden worldwide. Men with preexisting CVD have an increased risk for major adverse cardiovascular events when treated with androgen deprivation therapy (ADT). The present study aimed to explore the prevalence and risk evaluation of CVD among people with newly diagnosed PCa in China. Clinical data of newly diagnosed PCa patients were retrospectively collected from 34 centers in China from 2010 to 2022 through convenience sampling. CVD was defined as myocardial infarction, arrhythmia, heart failure, stroke, ischemic heart disease, and others. CVD risk was estimated by calculating Framingham risk scores (FRS). Patients were accordingly divided into low-, medium-, and high-risk groups. χ2 or Fisher's exact test was used for comparison of categorical variables. A total of 4253 patients were enrolled in the present study. A total of 27.0% (1147/4253) of patients had comorbid PCa and CVD, and 7.2% (307/4253) had two or more CVDs. The enrolled population was distributed in six regions of China, and approximately 71.0% (3019/4253) of patients lived in urban areas. With imaging and pathological evaluation, most PCa patients were diagnosed at an advanced stage, with 20.5% (871/4253) locally progressing and 20.5% (871/4253) showing metastasis. Most of them initiated prostatectomy (46.6%, 1983/4253) or regimens involving ADT therapy (45.7%, 1944/4253) for prostate cancer. In the present PCa cohort, 43.1% (1832/4253) of patients had hypertension, and half of them had poorly controlled blood pressure. With FRS stratification, as expected, a higher risk of CVD was related to aging and metabolic disturbance. However, we also found that patients with treatment involving ADT presented an originally higher risk of CVD than those without ADT. This was in accordance with clinical practice, i.e., aged patients or patients at advanced oncological stages were inclined to accept systematic integrative therapy instead of surgery. Among patients who underwent medical castration, only 4.0% (45/1118) received gonadotropin releasing hormone antagonists, in stark contrast to the grim situation of CVD prevalence and risk. PCa patients in China are diagnosed at an advanced stage. A heavy CVD burden was present at the initiation of treatment. Patients who accepted ADT-related therapy showed an original higher risk of CVD, but the awareness of cardiovascular protection was far from sufficient.

Treatment of Osteoporosis in Men on Androgen Deprivation Therapy in Japan.

Background and Objectives: Androgen deprivation therapy (ADT) for prostate cancer has greatly improved treatment outcomes. As patient survival rates have increased, reports of decreased bone density and increased bone fractures as side effects of ADT have emerged. The prevalence of osteoporosis in Japanese men was 4.6%. The purpose of this study was to evaluate the effect of osteoporosis treatment in prostate cancer patients who underwent ADT in Japan. Materials and Methods: The subjects were 33 male patients who had undergone ADT for prostate cancer, who were noted to have decreased bone density. Mean age was 76.2 ± 7.7 years (64-87). Medications included vitamin D in one case, bisphosphonates (BP) in 27 cases, and denosumab in five cases. The evaluation method examined the rate of change in bone mineral density (BMD) before osteoporosis treatment and 1 year after. For comparison, a group without osteoporosis treatment intervention (n = 33) was selected, and matched for prostate cancer treatment and age. The rate of change in trabecular bone score (TBS) was also calculated. Results: The percentage changes in BMD before and 1 year after treatment were as follows: lumbar spine, 7.1 ± 5.8% in the treatment group versus -3.9 ± 4.1% in the no treatment group; femoral neck, 5.5 ± 6.2% in the treatment group versus -0.9 ± 3.9% in the no treatment group; total femur, 6.6 ± 6.4% in the treatment group versus the no treatment group which was -1.7 ± 3.2%. In all cases, there was a clear significant difference (p < 0.01). The percent change in TBS was further calculated in the same manner. There was no significant difference between the two groups: +1.7 ± 3.8% in the treated group versus +0.3 ± 4.1% in the untreated group. Conclusions: Osteoporosis treatment in Japanese patients with prostate cancer on ADT therapy was found to significantly increase BMD compared to the untreated group. BP and denosumab were found to be very effective in increasing BMD.

Phase II study of pembrolizumab in combination with radiation with or without olaparib in localized high-risk prostate cancer.

TPS351 Background: Definitive radiation therapy (DRT) combined with androgen deprivation therapy (ADT) remains the standard of care in patients with high-risk prostate cancer (HRPC) who do not want surgery. However, up to 50% experience biochemical recurrence (BCR) within 5 years. A phase 3 NCIC group reported the 10-year biochemical recurrence free survival was 63% in ADT plus DRT vs. 27% in ADT alone. There is an urgent need for effective novel combination strategies. We hypothesize combined immune sensitizing effects of PARPi and radiation will result in significant activity of immunotherapy in men with HRPC. Methods: This is a multicenter phase II randomized study to assess biochemical response rates, safety and tolerability of combined therapy in pts with localized HRPC who elected for concurrent DRT. A total of 64 pts will be randomized 1:1 to receive either pembrolizumab (P) combined with olaparib or single agent P in addition to the standard of care ADT with DRT. Hypofractionated IMRT (2.4 to 4 Gy per fraction over 4-6 weeks) will be delivered and all pts will receive adjuvant P for one year and ADT for at least 18 months. All pts will undergo germline testing. Key eligible criteria include biopsy confirmed prostate adenocarcinoma who meets at least one of the four high-risk features: 1) clinical T3a, T3b or T4, 2) N1, 3) Gleason grade group 4 or 5, and 4) PSA &gt;20 ng/ml. Patients with less than 2 cm pelvic nodes and received ADT therapy within 3months prior to study enrollment are allowed. PSA &gt;150 ng/ml and patients with distant metastases will be excluded. The primary endpoint is to assess the proportion of patients who achieve a PSA nadir level of ≤ 0.06 ng/ml within six months after completion of radiation therapy in each arm. The secondary objectives include safety/tolerability, BCR and metastasis-free survival at 3 years. BCR is defined by the Phoenix definition. The study is designed to detect a 15% improvement in PSA nadir ≤ 0.06 ng/mL within 6 months after completion of the combined therapy versus historical control group data Geara FB et al., 2017. Enrollment began in August 2023. Clinical trial information: NCT05568550 .

Central Nervous System-related Conditions and Associated Healthcare Resource Use Among Japanese nmCRPC Patients Based on Retrospective Claims Data.

Background: Japanese patients with prostate cancer are typically treated with primary androgen deprivation therapy (ADT), most commonly administered as a combination of a luteinizing hormone-releasing hormone (LHRH) agonist and an antiandrogen (AA). Since LHRH agonists and AA therapy can be maintained for several years, the long-term effects of these treatments on patients must be carefully considered, including the risk of concomitant central nervous system (CNS) conditions which could affect treatment choices. Objective: To describe CNS-related concomitant conditions during ADT and/or AA treatment and the subsequent healthcare resource utilization in Japanese nonmetastatic castration-resistant prostate cancer (nmCRPC) patients. Methods: Patients diagnosed with nmCRPC and CNS-related conditions while on ADT and/or AA therapy between April 2009 and August 2017 were retrospectively followed up for a maximum of 2 years using a claims database. Results: A total of 455 patients (average age, 78.5 years), were included. The 3 most common concomitant CNS-related conditions were pain (~60% of events), insomnia (~30%), and headache (2%-3%). The frequency of CNS-related conditions in these patients increased approximately threefold after starting AA therapy (before, 969 events; after, 2802). On average, a patient had 10 episodes of concomitant CNS-related conditions in a year. Medical costs did not significantly increase due to CNS-related conditions. Discussion: The most frequently reported CNS-related conditions were pain, insomnia, and headaches. Furthermore, more concomitant CNS-related conditions 1 year after CRPC diagnosis and 1 year after starting AA treatment were recorded. Conclusion: Patients with nmCRPC experience an increase in the frequency of concomitant CNS-related conditions, including pain, insomnia, and headaches, after CRPC diagnosis or starting AA treatment. Future research should explore the causes of this increased frequency.

Central Nervous System-related Conditions and Associated Healthcare Resource Use Among Japanese nmCRPC Patients Based on Retrospective Claims Data

Background: Japanese patients with prostate cancer are typically treated with primary androgen deprivation therapy (ADT), most commonly administered as a combination of a luteinizing hormone-releasing hormone (LHRH) agonist and an antiandrogen (AA). Since LHRH agonists and AA therapy can be maintained for several years, the long-term effects of these treatments on patients must be carefully considered, including the risk of concomitant central nervous system (CNS) conditions which could affect treatment choices. Objective: To describe CNS-related concomitant conditions during ADT and/or AA treatment and the subsequent healthcare resource utilization in Japanese nonmetastatic castration-resistant prostate cancer (nmCRPC) patients. Methods: Patients diagnosed with nmCRPC and CNS-related conditions while on ADT and/or AA therapy between April 2009 and August 2017 were retrospectively followed up for a maximum of 2 years using a claims database. Results: A total of 455 patients (average age, 78.5 years), were included. The 3 most common concomitant CNS-related conditions were pain (~60% of events), insomnia (~30%), and headache (2%-3%). The frequency of CNS-related conditions in these patients increased approximately threefold after starting AA therapy (before, 969 events; after, 2802). On average, a patient had 10 episodes of concomitant CNS-related conditions in a year. Medical costs did not significantly increase due to CNS-related conditions. Discussion: The most frequently reported CNS-related conditions were pain, insomnia, and headaches. Furthermore, more concomitant CNS-related conditions 1 year after CRPC diagnosis and 1 year after starting AA treatment were recorded. Conclusion: Patients with nmCRPC experience an increase in the frequency of concomitant CNS-related conditions, including pain, insomnia, and headaches, after CRPC diagnosis or starting AA treatment. Future research should explore the causes of this increased frequency.

Abstract B004: Genomic loss of TP53 impairs AR-targeted activity in metastatic prostate cancer

Abstract Background: Metastatic prostate cancer (mPC) is notable for a spectrum of recurrent genomic alterations, some associated with overall prognosis and others predicting response to specific therapeutics. Standard mPC interventions are designed to suppress the signaling program regulated by the androgen receptor (AR). These include androgen deprivation therapy (ADT) to reduce AR ligand levels and AR signaling inhibitors (ARSI) that directly impair AR function. While ADT and ARSI produce clinical responses in most patients, the duration and depth of response vary greatly. In addition, specific recurring genomic alterations are associated with shorter responses after ADT and ARSI therapy. Among these are mutations and/or genomic copy loss involving key tumor suppressor genes, including PTEN, RB1 and TP53. However, the mechanistic contribution of TP53 loss to AR signaling and resistance to AR pathway-directed therapy remains unresolved. Methods: Isogenic prostate cancer cell lines with intact and TP53 deletions were constructed using CRISPR/Cas9. The transcriptome profiles were determined by RNA-seq, and ChIP-seq was used to determine the chromatin landscapes of AR localization. In addition, we performed ATAC-seq to assess chromatin accessibility. Finally, to further validate the findings, we comprehensively analyzed AR-regulated gene expression and AR cistromes across a panel of patient-derived xenograft (PDX) models and clinical cohorts of mPC patient samples with respect to TP53 status. Results: Compared to TP53-wild-type (WT) cells, the transcriptional results of isogenic knockout TP53 lines showed impaired AR canonical activity. However, the downregulated AR response pathway is not caused by reduced levels of AR transcript or protein levels. Additionally, a similar trend was also found while comparing TP53-WT PDX models with TP53-loss models. We found that the loss of TP53 can shift the chromatin binding of AR, and the altered AR binding sites correlated with genes involved in neurogenesis pathways, which provide a potential mechanism of how the loss of TP53 might impact AR signaling and promote ADT and ARSI treatment resistance. We also identified additional AR chromatin binding sites that were enriched due to the loss of TP53. The targets potentially regulated by these sites are involved in multiple pathways, including cell morphogenesis involved in differentiation and response to the endogenous stimulus. Conclusions and Future Directions: Overall, the results indicate that in addition to altering DNA damage and repair pathways and contributing to cancer progression, genetic loss of TP53 in mPC may directly impair ADT and ARSI therapies, partially through alteration of AR chromatin activity. In addition, the AR cistrome reprogramming resulting from TP53 loss could also affect other pathways that could be exploited to overcome ARSI treatment resistance. Citation Format: Wanting Han, Michael D. Nyquist, Ilsa Coleman, Navonil De Sarkar, Lisa Ang, Eva Corey, Peter S. Nelson. Genomic loss of TP53 impairs AR-targeted activity in metastatic prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B004.

Abstract B007: New generation mTOR blocker sensitizes prostate cancer models to AR-targeting therapy

Abstract Advanced stage prostate cancers (PCa) can develop bone metastasis, a lethal feature of castration-resistant prostate cancer (CRPC) for which no curative options are currently available. Androgen deprivation therapy (ADT) is the main therapeutic strategy for treating advanced PCa; patients with bone metastasis, however, are frequently developing resistance to ADT, progressing to CRPC. Dysregulation of the mTOR pathway has been linked with AR reactivation and with progression to CRPC, and mutations in targets of the PI3K/Akt/mTOR pathway are frequently found in CRPC patients. This study investigates the effect of synergistic AR and mTOR pathways blockade on therapy resistance in advanced PCa in vitro and in vivo. LNCaP and LAPC4 cells were treated in vitro with AR blockers (apalutamide, enzalutamide), mTOR blockers (rapamycin, everolimus, MLN0128 or Rapalink-1) or a combination of both blockers. Viability was measured in a timecourse from 1 to 10 days after drug administration using CellTiter Acqueous 96. To mimick ADT in vitro, cells were cultured for 7 days in charcoal-stripped serum in medium without dihydroxytestosterone or phenol red before the drug screening. Two already established PDX models of bone-metastatic PCa, BM18 and LAPC9 respectively androgen-dependent and -independent, were used to assess the effect of combined ADT and mTOR-targeting therapy in vivo. Both LNCaP and LAPC4 models showed a higher sensitivity to MLN0128 and Rapalink-1 compared to rapalogs, LAPC4 cells in particular were more sensitive than LNCaP cells to mTOR inhibitors. AR blockers were moderately effective and only at concentrations between 10 and 100 µM, when used alone. However, treatment with sublethal doses of Rapalink-1 (0.001-0.01 µM) sensitized both cell lines to 2- to 3-log fold lower concentrations of apalutamide. In vivo, treatment with Rapalink-1 alone significantly reduced the growth rate of LAPC9 PDX, while co-treatment with ADT and Rapalink-1 resulted in regression in this CRPC model, a result not achievable by either treatment alone. Treatment with Rapalink-1, while effectively reducing cell viability in vitro already when used alone, could sensitize the tested models to AR blockers, at clinically relevant concentrations. In vivo treatment with Rapalink-1 was well-tolerated and sufficient to control the growth of the BM18 PDX model. When used in combination with ADT, it could induce regression of the CRPC model LAPC9. Citation Format: Shuang Li, Federico La Manna, Panagiotis Chouvardas, George Thalmann, Marianna Kruithof-de Julio. New generation mTOR blocker sensitizes prostate cancer models to AR-targeting therapy [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B007.

Effect of Serelys Homme on the Incidence and Severity of Vasomotor Symptoms and Quality-of-Life Impairments in Patients Receiving Hormone Therapy and Radiation for Localized Prostate Cancer: Results of the ESCULAPE Phase 2 Prospective Study

Androgen deprivation therapy (ADT) may cause vasomotor symptoms (VMS) including hot flushes and sweats, which affect quality of life (QoL). Serelys Homme is a nonhormonal and a natural origin product that could affect VMS in men undergoing ADT. We evaluated effectiveness and tolerance of Serelys Homme administration on VMS and QoL of patients undergoing combined ADT and radiation therapy for prostate cancer. Between April 2017 and July 2019, 103 patients were screened, and 53 patients refused to participate in the study. Serelys Homme therapy consisted of a daily administration of 2 tablets for 6 months. Patients were evaluated with 4 questionnaires including the adapted Modified Rankin Scale (adapted-MRS), European Quality of Life 5 Dimensions 3 Level Version (EQ 5D3L), Functional Assessment of Cancer Therapy-Prostate (FACT-P), and Hot Flash Related Daily Interference Scale (HFRDIS) at day 0, day 90 (D90), and day 180 (D180). Statistical evaluation was performed using the Wilcoxon rank sign test. A 2-sided P < .05 was considered statistically significant. Among the 50 patients, 4 withdrew after inclusion. All patients (n=46) received either postoperative or definitive radiation therapy combined with a short (n=15) or long course (n=31) of ADT. Serelys Homme administration significantly decreased the rate of patients who had ≥7 VMS and 3 to 6 VMS per day. The number of patients presenting with moderate or severe VMS was decreased at D90 (P=.005) and at D180 (P=.005). In addition, VMS duration was reduced at D90 (P=.002) and D180 (P < .001). Finally, at D90 and D180, 11.1% and 16.0% of patients, respectively, with initial severe or moderate VMS had a complete response without further symptoms. Among QoL parameters, fatigue decreased significantly. Effectiveness evaluated by doctors was rated as moderate or good to excellent VMS control in 20% and 60% of the patients, respectively. No side effects were recorded in the whole population. This study demonstrated effectiveness and excellent tolerance of Serelys Homme. We observed a significant reduction of the frequency, duration, and intensity of hot flushes and sweats induced by ADT. Serelys Homme increased QoL scores. These encouraging results open the prospect to further studies and Serelys Homme use in patients undergoing ADT for prostate cancer.

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.

MP78-20 EFFECT OF HYPOGONADISM ON OUTCOMES FOLLOWING ARTIFICIAL URETHRAL SPHINCTER IMPLANTATION

You have accessJournal of UrologyCME1 Apr 2023MP78-20 EFFECT OF HYPOGONADISM ON OUTCOMES FOLLOWING ARTIFICIAL URETHRAL SPHINCTER IMPLANTATION Zachary Pfeifer, Rano Matta, Joshua Horns, Nathan Driggs, Benjamin McCormick, James Hotaling, Kevin Hebert, and Jeremy Myers Zachary PfeiferZachary Pfeifer More articles by this author , Rano MattaRano Matta More articles by this author , Joshua HornsJoshua Horns More articles by this author , Nathan DriggsNathan Driggs More articles by this author , Benjamin McCormickBenjamin McCormick More articles by this author , James HotalingJames Hotaling More articles by this author , Kevin HebertKevin Hebert More articles by this author , and Jeremy MyersJeremy Myers More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003355.20AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The artificial urinary sphincter (AUS) has been the gold standard management in male stress urinary incontinence for the last 50 years. The most common complications requiring re-intervention include infection and erosion. Risk of late revision surgery or device removal range from 20-50%. Hypogonadism has been shown to impair wound healing and has been hypothesized to impact AUS device survival. Thus we sought to assess the incidence of AUS revision or removal in the setting of hypogonadism. METHODS: Using IBM MarketScan, a commercial claims database, patients undergoing AUS were identified using Current Procedural Terminology (CPT) and ICD-10 procedure codes between 2008 and 2017. ICD-9/10 codes were used to identify patients with pre-operative diagnoses of hypogonadism. National drug codes (NDCs) and J-Codes were used to identify patients undergoing androgen deprivation therapy (ADT) or testosterone replacement therapy (TRT). Incident rate ratios (IRR) were assessed using a multivariate model to determine association of hypogonadism with AUS revision and/or explantation. RESULTS: A total of 2740 men were identified that underwent primary AUS implantation of which 2228 had no prior history of hypogonadism or ADT therapy and were considered eugonadal. 512 (18.7%) men were hypogonadal or receiving TRT including active ADT 369 (13.5%) men, 92 (3.4%) hypogonadal without TRT, and 51 (1.9%) active TRT. On multivariate analysis, untreated hypogonadism (IRR 1.56; 95% CI [1.0-2.3]) was associated with an increased likelihood of re-operation when controlling for covariates. Active ADT (IRR 0.91; 95% CI [0.72-1.14]) and hypogonadism with active TRT (IRR 1.147; 95% CI [0.55-2.10] were not associated with increased risk of reoperation. CONCLUSIONS: In a cohort of 2740 patients undergoing primary AUS placement, untreated hypogonadism was associated with an increased likelihood of re-operation. TRT and ADT at the time of AUS surgery were not associated with increased rates of reoperation. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1139 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Zachary Pfeifer More articles by this author Rano Matta More articles by this author Joshua Horns More articles by this author Nathan Driggs More articles by this author Benjamin McCormick More articles by this author James Hotaling More articles by this author Kevin Hebert More articles by this author Jeremy Myers More articles by this author Expand All Advertisement PDF downloadLoading ...

Androgen Deprivation Therapy for Prostate Cancer Influences Body Composition Increasing Risk of Sarcopenia

Computed tomography (CT) scans used in treatment response assessment in prostate cancer (PCa) patients are a useful tool for nutritional status evaluation. The aim of this study was to assess the nutritional status, including sarcopenia development based on CT scans, in PCa patients and its association with progression-free survival (PFS). Sixty-four PCa patients were included (group 1: 34 patients undergoing androgen deprivation therapy (ADT) with docetaxel due to newly diagnosed, hormone-sensitive, metastatic PCa and group 2: 30 patients with castration-resistant metastatic PCa continuing ADT therapy with enzalutamide or abiraterone acetate). Nutritional status was evaluated with anthropometrical parameters, Nutritional Risk Score (NRS), and CT scans at the L3 vertebrae. Survival analyses were performed. According to NRS, nutritional status was significantly related to PFS. In both groups, there was a significant reduction in muscle tissue (total muscle tissue and skeletal muscle index). A significant increase in the distribution of adipose tissue (subcutaneous fat, visceral fat, subcutaneous adipose tissue index, and visceral adipose tissue index) in group one was observed. Sarcopenia was diagnosed in patients but with no influence on PFS. Significant reduction in muscle mass and increase in fat mass was observed in patients treated for PCa with no impact on PFS. The NRS was related to PFS in PCa patients and associated with body composition, assessed by CT after the castration therapy. Long-term castration combined with abiraterone therapy with prednisone or enzalutamide significantly influenced muscle tissue and may lead to sarcopenia development.

Effect and Mechanism of lncRNA-PCMF1/hsa-miR-137/Twist1 Axis Involved inthe EMTRegulation of Prostate Cancer Cells.

The metastasis is a majorreason for the poor prognosis of the patients with prostate cancer (PC). Currently, androgen deprivation therapy (ADT) is the basic method for the treatment of PC regardless of surgery or drug treatments. However, ADT therapy is generally not recommended for patients with advanced/metastatic PC. Herein, wereportforthefirsttime a long non-coding RNA (lncRNA)-PCMF1 which promotes the progression of Epithelial-Mesenchymal Transition (EMT) in PC cells. Our data demonstrated that PCMF1 in metastatic PC tissues increased significantly compared to non-metastatic specimens. Mechanismresearchshowedthat PCMF1 could competitively bind to hsa-miR-137 instead of the 3' -Untranslated Region (UTR) of Twist Family BHLH Transcription Factor 1 (Twist1) by acting as an endogenous miRNA sponge. Furthermore,we found that silence of PCMF1 effectively blocked the EMT in PC cells by indirectly suppressing Twist1 protein mediated by hsa-miR-137 at post-transcriptional level. In summary, our research shows that PCMF1 promotes the EMT of PC cells by causing the functional inactivation of hsa-miR-137 on Twist1 protein, which is an independent risk factor of PC. PCMF1 knockdown combined with hsa-miR-137 expression is a promising PC-targeted therapy. Furthermore, PCMF1 is also expected toactas a useful marker for predicting malignantchanges and assessing the prognosis of PC patients.

Is it Necessary to Treat all Metastatic Prostate Cancer With Upfront Androgen Receptor Axis-targeted Agents?

In recent years, initial treatment for patients with high-risk metastatic castration-sensitive (mCS) prostate cancer (PC) has been shifting from vintage hormone therapy to upfront androgen receptor axis-targeted agents (ARAT), but the proportion of Asian patients enrolled in clinical trials investigating the effectiveness of ARAT use is low. We examined the outcomes of Japanese patients with mCSPC who received ARAT as second-line therapy or afterwards. Among the PC patients receiving treatment at Kanazawa University Hospital from 2000 to 2019, 190 patients with mCSPC were enrolled in the study. Their characteristics and prognosis were retrospectively investigated. All patients received androgen deprivation therapy (ADT) as initial treatment. A total of 142 (74.3%) of 190 patients had progression to castration-resistant PC (CRPC), of whom 77 (54.2%) received ARAT as second-line therapy or afterwards. The median overall survival (OS) of CRPC patients was 70.57 months and the median OS from CRPC was 44.88 months. The median OS of LATITUDE high-risk patients that used ARAT after the second-line treatment was 56.15 months, which was significantly longer than that of patients who did not use ARAT (hazard ratio=0.68, 95% confidence interval=0.40-1.15; p=0.0089). The prognosis of LATITUDE high-risk patients with CRPC selected for initial ADT therapy had a good prognosis compared to findings in other studies. These results suggest that there is a possibility that a certain number of patients with LATITUDE high-risk may have good prognosis even if only conventional ADT is performed and ARAT is used after CRPC.

Dual-energy x-ray absorptiometry assessment of bone health in Australian men with prostate cancer commencing androgen deprivation therapy.

To determine the prevalence in Australia of bone health assessment of men with prostate cancer by dual-energy x-ray absorptiometry (DXA), from six months before to twelve months after initiation of androgen deprivation therapy (ADT). Cross-sectional national study; linkage of de-identified Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Scheme (PBS) data. Men (18 years or older) first dispensed PBS-subsidised ADT during 1 May 2017 - 31 July 2020. Prevalence of MBS-subsidised DXA assessments undertaken from six months before to twelve months after first ADT prescription. Of 33 836 men with prostate cancer commencing ADT therapy during 2017-20, 6683 (19.8%) underwent DXA bone heath assessments between six months before and twelve months after commencing ADT; the mean time from first ADT dispensing to DXA scanning was +90 days (standard deviation, 134 days). The proportion of men aged 54 years or younger who had scans (66 of 639, 10%) was smaller than that of men aged 70-84 years (4528 of 19 378, 23.4%; adjusted odds ratio, 0.36; 95% CI, 0.28-0.47). For about 80% of men with prostate cancer commencing ADT in Australia, therapy initiation was not accompanied by DXA assessment of bone health. Given the excellent long term prognosis for men with prostate cancer and the availability of bone protective therapy, bone health monitoring should be a routine component of prostate cancer care for men receiving ADT.

Androgen deprivation therapy duration is significantly associated with Testosterone recovery in Japanese patients with prostate cancer.

Due to the fear generated by COVID-19 in Spring 2020, many patients postponed their scheduled outpatient visits. To differentiate those patients with prostate cancer (PCa) whose androgen deprivation therapy (ADT) injection treatment can be postponed, we investigated the characteristics of testosterone (T) recovery in Japanese patients after they received combined ADT and radiation therapy (RT). We included 81 patients with PCa treated with ADT and RT at Keio University Hospital from January 2013 to December 2018. T-recovery was defined as the time interval between the last ADT injection and 3-6months after T-normalization. The Kaplan-Meier method was used to estimate time to T-recovery. Cox proportional hazards models identified T-recovery predictors. The 50% cumulative incidence of T-recovery was 7.0months for the 6-short-term group (defined as patients having ≤6months of ADT therapy) versus 13.0months for the 6-long-term group (>6months of therapy) (p < 0.001). The incidence was 7.0months for the 12 short-term-ADT (ST) group versus 18.0months for the 12 long-term-ADT (LT) group (p < 0.001). Multivariate analysis revealed that a shorter duration of ADT was associated with a shorter time to T-recovery (hazard ratio, 0.253; 95% CI, 0.138-0.465; p < 0.001). No other factors were significant predictors of T-recovery. Androgen deprivation therapy duration is significantly associated with T-recovery in Japanese patients with PCa. If a patient undergoes ADT for more than 6 or 12months, it is possible to postpone their outpatient visits for 13 and 18months, respectively.

Cardiac risk factors and events in patients with prostate cancer commencing androgen deprivation therapy: analysis from a tertiary care centre in the Middle East.

Androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer, improving symptoms and prolonging survival. There is an association between ADT use and cardiovascular (CV) events, particularly in patients with preexisting risk factors. In men diagnosed with prostate cancer, CV disease is the principal non-cancer-related cause of death. There are no definite guidelines to stratify patients based on CV risk prior to ADT initiation. This is the first study on cardiac risks and events in patients with prostate cancer treated with ADT from the Middle East region, a population known to have a high prevalence of CV risk factors. A retrospective study of 234 patients with prostate cancer, who received ADT therapy at a tertiary care centre in Lebanon was conducted. CV risk factors at baseline and CV events on ADT were reviewed. The median age was 68 years (48-92 years). The majority of patients had stage 4 diseases at diagnosis (49.6%) with a median duration of 12 months on ADT. In our cohort, 24.4% had body mass index > 30, 52.1% had smoking history, 25.6% were diabetic, 19.7% had history of coronary artery disease, 9.8% had heart failure history and 52.9% had hypertension. Less than half of the patients had a documented lipid profile at baseline. Twenty-two patients (9.5%) had documented cardiac events following ADT initiation. In this cohort of patients from the Middle East, we found that one third of the population had established coronary artery disease at baseline and 9.5% had documented cardiac events on ADT initiation. Our study highlights the gaps in CV risk assessment for this high-risk group of patients with prostate cancer in addition to high prevalence of CV comorbidities. Risk and resource-stratified algorithms are needed before starting ADT therapy for optimal CV health. Increased awareness, collaboration and referral mechanisms between oncologists, urologists and cardiologists are also needed to provide optimal care.

Focal radiation with pulsed systemic therapy of abiraterone, androgen deprivation therapy (ADT), olaparib towards castration-sensitive oligometastatic prostate cancer (FAALCON Trial).

TPS5113 Background: Molecular imaging (i.e. PSMA directed agents) identifies metastatic prostate cancer at an earlier disease state than conventional imaging resulting in a new clinical entity within metastatic hormone-sensitive prostate cancer (mHSPC): molecular positive HSPC (mpHSPC). Historically, patients in this category with prior local therapy would have been classified as having a biochemical recurrence only, and observation was routine. Approaches to mpHSPC include observation or the use of focal and/or systemic therapies. Focal radiation for mpHSPC may delay the need for systemic therapy, yet many patients require further focal or systemic treatment. Androgen deprivation therapy (ADT) with abiraterone (abi) benefits men with high-risk localized disease and standard mHSPC. mpHSPC hypothetically resides somewhere between these two disease states. Finally, the inhibition of poly(ADP-ribose) polymerase (PARP) with olaparib plus abi shows promise in metastatic castration resistant prostate, suggesting this approach may be worthy of testing in earlier disease states. Methods: FAALCON is a single-site, phase 2 clinical trial testing olaparib with abi, ADT and radiation therapy in oligometastatic mpHSPC. Oligometastatic mpHSPC is defined as up to 5 radiation treatment sites (5 cm maximum size each) and must encompass all visible disease on the molecular scan. Patients must have had their prostate previously treated. The primary endpoint is the percentage of patients without treatment failure 24 months from study start. Treatment failure is defined as one of the following: new or progressive metastases on CT/MRI, new lesions on bone scan without alternate explanation, clinical progression, or a PSA doubling time under 6 months with an absolute final PSA over 1.5 ng/mL. Additional radiation therapy is deemed progression. Select secondary endpoints include time to any subsequent therapy, and percentage of patients with undetectable PSA with a recovered testosterone at multiple timepoints. Correlative work will analyze quality of life and prior prostatic tissue. ADT and abi (1000 mg daily) are given for 6 months, and radiation is completed by day 40. Olaparib (300 mg PO twice daily) is started 2 weeks after radiation completes and continues for the remaining ̃5 months. After therapy completion, patients are monitored by PSA q3 months with imaging based on predetermined PSA cutoffs. Molecular imaging (PSMA-PET) may be offered on study. Historical disease control at 24 months is estimated at 40% from prior molecular guided radiation studies and intermittent ADT. With 80% power and a one-sided 5% type-I error, we can detect a hazard ratio of 0.5 (80% control rate) at 24 months with 26 patients. To account for dropout, 29 patients will be accrued. Clinical trial information: NCT04748042.

Эффективность применения золедроновой кислоты при лечении остеопороза у больных раком предстательной железы, получающих терапию агонистами ГнРГ

Introduction. It has been established that prolonged androgen-deprivation therapy (ADT) of prostate cancer leads to a decrease in bone mineral density (BMD) and increases the risk of fractures, which is an important medical and social problem. Zoledronic acid (ZA) is most often used for the prevention of osteoporosis against the background of ADT. The purpose of the study is to determine the efficacy and safety of ZA for the treatment and prevention of osteopo-rosis in non-metastatic prostate cancer against the background of ADT therapy with GnRH agonists. Materials and methods. The study included 45 men aged 54-81 years with morphologically verified prostate cancer (stages T2-4 N0-1 M0) who underwent surgical castration at least 6 months before inclusion or continuously received therapy with GnRH agonists. The blood level of CTX-1 was used as the main marker of bone resorption. To assess the BMD, the screening method of dual-band X-ray densitometry of the calcaneus with laser determination of the examination area – DXL using the CALSCAN apparatus and the DXL Calscan Workstation software was used. Patients were randomized into groups of 15 people each: Group 1 – received intravenous infusion of ZA at a dose of 4 mg at the beginning of the study and after 3 months of treatment; Group 2 received ZA at 2 mg in the same mode; Group 3 – control. For antire-sorptive therapy (ART), the drug Resorba (JSC «Pharm-Synthesis», Russia) was used. The duration of follow-up was 6 months. Results. In 13 out of 15 patients of Group 1, 3 months after the first administration of ZA, a decrease in the level of CTX-1 by 50% or more was observed, and after 6 months all 15 patients (100%) reached the age norm («complete answer»). Group 2 patients also responded to ART and by the 6th month 13 out of 15 (87%) had achieved a «complete response». In the control group by the 6th month the decrease in CTX-1 was not observed in any of the patients. Initially, the values of BMD in the studied groups did not differ. By the 3rd month of the study, the BMD index significantly increased only in Group 1. In Group 2 this indicator significantly increased by the 6th month of treatment. At the same time, in Group 1 after 6 months the BMD index reached higher values than in Group 2: an increase of 27% and 13%, respectively. In the control group, by the 6th month of observation, a significant decrease in BMD by 12% was noted. In Group 1, the number of patients with osteoporosis decreased to 6% and with a normal level of BMD – reached to 40%. Conclusion. High efficacy and sufficient safety of ZA in doses of 4 mg and 2 mg i/v one time in 3 months for anti-resorptive therapy in patients receiving long-term hormonal therapy with GnRH agonists has been demonstrated.

The Effects of Statins on Prostate Cancer Patients Receiving Androgen Deprivation Therapy or Definitive Therapy: A Systematic Review and Meta-Analysis.

Mortality associated with statin use has been reported in prostate cancer (PCa) patients treated with androgen deprivation therapy (ADT) or definitive therapy in several observational studies, although the results have varied. This study aimed to analyze the association of statin use with all-cause mortality and cancer-specific mortality among PCa patients receiving ADT or definitive therapy as their primary treatment and to examine the effect of statin initiation (pre-ADT) timing on outcomes. A systematic literature search of PubMed, the Cochrane library, and Embase was conducted from database inception to 4 October 2021. In total, 12 eligible studies from 976 references were included in the final analysis. The results showed that statin use was associated with a significant reduction in the risks of all-cause mortality (hazard ratio (HR) = 0.73, 95% confidence interval (CI) = 0.64–0.84, p < 0.0001) and cancer-specific mortality (HR = 0.61, 95% CI = 0.49–0.77, p < 0.0001) in PCa patients receiving ADT. However, statin use before ADT initiation did not significantly lower the risk of all-cause mortality (HR = 0.87, 95% CI = 0.66–1.16, p = 0.35) or cancer-specific mortality (HR = 0.84, 95% CI = 0.62–1.13, p = 0.25) in advanced PCa patients receiving ADT. In contrast, statin use was not associated with a significantly reduced risk of all-cause mortality (HR = 0.69, 95% CI = 0.39–1.21, p = 0.20), but it was associated with a reduced risk of cancer-specific mortality (HR = 0.82, 95% CI = 0.68–0.98, p = 0.03) in PCa patients receiving definitive therapy. This review indicated that statin use in combination with ADT was correlated with better all-cause and cancer-specific mortality in PCa patients. However, the beneficial effect might not come from statin use before ADT initiation. In addition, statin use in combination with definitive therapy was correlated with a reduced risk of cancer-specific mortality in PCa patients. In the future, randomized controlled trials are needed to validate the efficacy of statin use in combination with primary treatment for PCa among PCa patients.

Association of Short-Term Patient-Reported Outcomes With Long-Term Oncologic Outcomes in Localized Prostate Cancer Patients Treated With Radiation Therapy and Androgen Deprivation Therapy in a Randomized Controlled Trial

PurposeBoth oncologic outcomes and patient-reported outcomes are pivotal in prostate cancer (PCa). However, it remains unknown if there is any association between these 2 outcomes. In this secondary analysis of a randomized controlled trial, we investigated the association of short-term changes in patient-reported outcome with long-term event-free survival (EFS) and metastasis-free survival (MFS) in localized PCa. Methods and MaterialsLocalized PCa patients with a Gleason score ≤7, clinical stage T1b to T3a, and prostate-specific antigen (PSA) <30 ng/mL were randomized to neoadjuvant and concurrent androgen deprivation therapy (ADT) for 6 months starting 4 months before prostate radiation therapy or concurrent and adjuvant ADT for 6 months starting simultaneously with radiation therapy. Patient-reported symptom burden was evaluated using the European Organisation for Research and Treatment of Cancer quality of life questionnaire (QLQ)-PR.25. Clinically meaningful deterioration (CMD) was defined as a ≥10-point worsening at any time within 10 months postrandomization regardless of subsequent improvement. Landmark analyses were performed to determine the association of CMD of urinary and bowel symptoms separately with EFS and MFS in patients who responded to the baseline questionnaire, were alive, and were event free at 10 months. ResultsOverall, 393 patients had responded to the baseline QLQ. One patient died, and 1 patient had failure within 10 months. Therefore, 391 patients were eligible for the landmark analyses. After adjusting for age, Gleason score, PSA, performance status, and treatment group, CMD of urinary symptoms was associated with worse EFS (hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.21-2.65) and MFS (HR, 1.69; 95% CI, 1.11-2.57). Considering deaths as competing events, CMD of urinary symptoms was associated with a significant increase in the relative incidence of progression (subdistribution HR, 2.42; 95% CI, 1.12-5.20). However, no association was found between CMD of bowel symptoms and EFS or MFS. ConclusionsIn this study, short-term CMD of urinary symptoms was associated with significantly inferior EFS and MFS and an increase in the relative incidence of progression. Further investigations are needed to explore the biological rationale of such association in the context of ADT and radiation therapy.