First-generation Antiandrogens Research Articles

PSMA PET/CT SUVmax as a prognostic biomarker in patients with metachronous metastatic hormone-sensitive prostate cancer (mHSPC).

Metastatic hormone-sensitive prostate cancer (mHSPC) is treatment-resistant and generally considered incurable. The development of prostate-specific membrane antigen positron emission-computed tomography (PSMA PET/CT) has generated immense expectations due to its diagnostic accuracy in prostate cancer (PCa). PSMA expression of the primary tumor, quantified by SUVmax, is a predictor of oncological outcomes. The role of PSMA-PET/CT SUVmax in metachronous mHSPC treated with ADT plus second-generation antiandrogens (ARSI) is unknown. The main aim of this study was to evaluate 68Ga-PSMA-11expression (SUVmax) as a potential prognostic biomarker in patients with metachronous mHSPC treated with ADT and first or second-generation antiandrogens. A second aim was to determine the association between PSMA SUVmax and PSA response to hormone therapy. Patients diagnosed with metachronous mHSPC between July 2017 and February 2023 who developed biochemical recurrence following radical surgery (with or without salvage radiotherapy and/or ADT) or external radiation therapy (with or without ADT) were included. All patients underwent 68Ga-PSMA-11 PET/CT imaging and the SUVmax value was determined for all measurable locations. The SUVmax value was used for the semiquantitative analysis. The Wilcoxon method was used to compare responders (PSA reduction ≥ 50%) to non-responders (PSA reduction < 50%). The SUVmax value and hormone therapy were evaluated as independent variables relative to the PSA response rate or PSA reduction using the linear regression method. A mixed-effects model (ANOVA) was used for the comparisons. A total of 82 patients were included. Median follow-up was 11.7 months. On the linear regression analysis, patients with a high SUVmax treated with ADT + ARSI showed a greater PSA response (p = 0.034) than those treated with ADT + first-generation antiandrogens. In the mixed-effects model, SUVmax was significant (p = 0.041). On the univariate analysis, PSA at recurrence (HR, 3.2; 95% CI: 1.07-13.6; p = 0.078) and the number of metastases (HR, 4.77; 95% CI 1.1-26.1: p = 0.002) were associated with the type of hormone therapy administered. PSMA-PET/CT SUVmax is a prognostic biomarker that can be used to predict a PSA response to ADT + ARSI in patients with metachronous mHSPC. However, these findings need to be confirmed in larger prospective studies.

A novel prognostic model of de novo metastatic hormone-sensitive prostate cancer to optimize treatment intensity.

The treatment and prognosis of de novo metastatic hormone-sensitive prostate cancer (mHSPC) vary. We established and validated a novel prognostic model for predicting cancer-specific survival (CSS) in patients with mHSPC using retrospective data from a contemporary cohort. 1092 Japanese patients diagnosed with de novo mHSPC between 2014 and 2020 were registered. The patients treated with androgen deprivation therapy and first-generation anti-androgens (ADT/CAB) were assigned to the Discovery (N = 467) or Validation (N = 328) cohorts. Those treated with ADT and androgen-receptor signaling inhibitors (ARSIs) were assigned to the ARSI cohort (N = 81). Using the Discovery cohort, independent prognostic factors of CSS, the extent of disease score ≥ 2 or the presence of liver metastasis; lactate dehydrogenase levels > 250U/L; a primary Gleason pattern of 5, and serum albumin levels ≤ 3.7g/dl, were identified. The prognostic model incorporating these factors showed high predictability and reproducibility in the Validation cohort. The 5-year CSS of the low-risk group was 86% and that of the high-risk group was 22%. Approximately 26.4%, 62.7%, and 10.9% of the patients in the Validation cohort defined as high-risk by the LATITUDE criteria were further grouped into high-, intermediate-, and low-risk groups by the new model with significant differences in CSS. In the ARSIs cohort, high-risk group had a significantly shorter time to castration resistance than the intermediate-risk group. The novel model based on prognostic factors can predict patient outcomes with high accuracy and reproducibility. The model may be used to optimize the treatment intensity of de novo mHSPC.

Treatment patterns and healthcare resource utilization in patients with metastatic hormone-sensitive prostate cancer and nonmetastatic castration-resistant prostate cancer in China: a real-world observational study

Aim This study assessed the treatment patterns, healthcare resource utilization (HRU), costs, and annual prevalence and incidence of metastatic hormone-sensitive prostate cancer (mHSPC) and nonmetastatic castration-resistant prostate cancer (nmCRPC) in China. Methods A retrospective study was conducted using electronic medical records (EMR) of patients with prostate cancer from three tertiary-care hospitals in China between January 2014 and March 2021. Descriptive statistics were used to analyze study outcomes. Results In total, 1086 patients with mHSPC and 679 patients with nmCRPC were included. From 2015 to 2020, the annual percentage of prevalent and incident cases of mHSPC decreased from 22.4% to 20.0% and 11.1% to 6.9%, respectively; for nmCRPC, these increased from 3.8% to 13.6% and 3.3% to 8.4%. Androgen-deprivation therapy and first-generation antiandrogens (bicalutamide or flutamide) were the most frequently prescribed prostate cancer–related medications at baseline and follow-up in patients with mHSPC. Bicalutamide was the most frequently prescribed prostate cancer–related medication during follow-up in patients with nmCRPC. For mHSPC, inpatient admission costs were the highest, with the median (interquartile range) costs per person-month being USD 403.00 (USD 85.50–1226.20), whereas outpatient visit costs were the highest for nmCRPC (USD 372.60 [USD 139.50–818.50]). Limitations EMR-based study design did not capture treatment patterns, HRU and associated costs, and healthcare encounters that occurred outside of participating hospitals, which could have led to underestimation of the true disease burden. Conclusions A contrasting trend of a decline in the prevalence and incidence of mHSPC and an increase in these for nmCRPC was observed between 2015 and 2020 in China. Androgen-deprivation therapy and first-generation antiandrogens were the most frequently prescribed prostate cancer–related medications. Healthcare resource utilization was driven by inpatient costs in mHSPC and outpatient costs in nmCRPC.

Prostate-specific antigen (PSA) response among patients with metastatic castration-sensitive prostate cancer (mCSPC) initiated on apalutamide (APA) or abiraterone acetate (ABI) in real-world urology practices.

53 Background: Recently approved oral therapies APA and ABI (plus prednisone) are effective mCSPC treatments. Prior real-world evidence showed that, relative to ABI, patients who initiated APA had significantly higher rates of PSA decline ≥90% (PSA90), which has been associated with longer overall survival. The objective of this study was to compare PSA90 response among an enhanced cohort of patients with mCSPC initiated on APA or ABI. Methods: Electronic medical records from PPS Analytics including data from US community urology practices were linked with administrative claims from the Komodo Health Solutions Research Database. Androgen receptor signaling inhibitor (ARSI)-naïve patients with mCSPC with ≥12 months of pre-index clinical activity were selected into the APA or ABI cohort based on their first paid claim/dispensation on or after 17 Sep 2019 (index date). Patients were followed to earliest of index ARSI discontinuation or switch, radiopharmaceutical use, end of insurance or clinical activity, or end of data availability (30 Sep 2022). Inverse probability treatment weighting (IPTW) was used to reduce potential pre-index confounding, controlling for age, race, region, insurance payer, index year, time from metastasis to index date, time from first prostate cancer (PC) diagnosis to index date, metastasis locations, de novo PC, use of androgen deprivation therapy, first-generation antiandrogens or chemotherapy, most recent PSA and testosterone levels, and most recent Gleason score. PSA90 was defined as the earliest attainment of ≥90% decline in PSA relative to pre-index (most recent value within 13 weeks). The proportion of patients achieving PSA90 was compared using a weighted Kaplan-Meier analysis and the time-to-PSA90 response was compared using a weighted Cox proportional hazards model. Results: A total of 917 APA and 632 ABI patients were identified. Patient characteristics were balanced with IPTW (Table). By 6 months post-index, 80.9% of APA and 72.8% of ABI patients had a PSA measurement. By 6 months, significantly more APA patients attained a PSA90 response, as compared to ABI patients (P &lt; 0.001; Table). Median time-to-PSA90 was 3.5 months for APA patients and 8.8 months for ABI patients. Conclusions: This real-world study supports previous findings that a greater percentage of patients with mCSPC in the US initiating APA achieved deep PSA response compared to those initiating ABI. [Table: see text]

Drug Resistance and Cardiovascular Safety of Second-Generation Anti-Androgens in Patients with Advanced Prostate Cancer

Prostate cancer is recognized as one of the most common cancers affecting the male population. The prostate is revealed to be a hormone-dependent tissue as testosterone and dihydrotestosterone could bind to the androgen receptor, activate it, and initiate the nuclear translocation of this receptor which is followed by subsequent signaling cascades. Regarding this androgen dependency of the prostate, it is believed that androgen deprivation therapies are able to confront aggressive prostate cancer as first-line treatment. However, prostate cancer could overcome hormone deprivation strategies through a number of cellular mechanisms, such as intratumoral androgen production and the production of ligand-independent androgen receptor splice variants, which are known clinically as castration-resistant prostate cancer. Due to the limited efficacy of first-generation antiandrogens in complete blockage of androgen receptor activity, recently, four second-generation anti-androgens, including abiraterone acetate, enzalutamide, apalutamide, and darolutamide approved by the Food and Drug Administration, and considered standard of care for patients with advanced prostate cancer. Nevertheless, prostate cancer cells may acquire drug-resistance mechanisms to overcome these novel chemotherapeutics. Furthermore, potential adverse effects on nontargeted organs such as the cardiovascular system, are possible. Hence, the current study aimed to review the efficacy and cardio-safety of these novel therapeutical strategies.

Calcium Activation of the Androgen Receptor in Prostate Cells.

Although prostate cancer patients initially respond to androgen deprivation therapy, most patients progress to a resistant phenotype. Castration resistance is due, in part, to intratumoral and/or adrenal synthesis of androgens, overexpression or mutation of the androgen receptor (AR), stabilization of AR by chaperones, and ligand-independent activation of AR. Increasing evidence also links disruption of calcium homeostasis to progression of prostate cancer. Our previous study shows that heavy metal cadmium activates the AR through a ligand-independent mechanism. Cadmium mimics calcium in biological systems due to their similar ionic charge and radius. This study determines whether calcium activates AR and whether first- and second-generation antiandrogens block the ability of calcium to activate the receptor. The expression of androgen-responsive genes and calcium channels was measured in prostate cells using a quantitative real-time polymerase chain reaction assay. Cell growth was measured. To ask whether calcium activates AR, prostate cells were treated with calcium in the absence and presence of the first-generation antiandrogens hydroxyflutamide and bicalutamide and the second-generation antiandrogen enzalutamide, and the expression of androgen-responsive genes and cell growth was measured. In the normal PWR-1E cells and HEK293T cells transiently expressing AR, treatment with calcium increased the expression of androgen-responsive genes by approximately 3-fold. The increase was blocked by enzalutamide but was not consistently blocked by the first-generation antiandrogens. In LNCaP cells which contain a mutant AR, treatment with calcium also increased the expression of androgen-responsive genes by approximately 3-fold, and the increase was more effectively blocked by enzalutamide than by hydroxyflutamide or bicalutamide. Treatment with calcium also increased cell growth that was blocked by enzalutamide. To ask whether dysregulation of calcium channels is associated with castration resistance, calcium channels were measured in the normal PWR-1E prostate cells, the hormone-responsive LNCaP cells, and the castration-resistant VCaP and 22RV1 cells. Compared to normal prostate cells, the hormone-responsive and hormone-resistant cells overexpressed several calcium channels. The results of this study show that calcium activates AR and increases cell growth and that calcium channels are overexpressed in hormone-responsive and hormone-resistant prostate cancer cells. Taken together, the results suggest a novel role of calcium in the castration-resistant phenotype.

Research protocol to identify progression and death amongst patients with metastatic hormone-sensitive prostate cancer treated with available treatments: PIONEER IMI's "big data for better outcomes" program.

Androgen deprivation therapy-based with or without first-generation anti-androgens, was the standard of care for patients with metastatic hormone-sensitive prostate cancer (mHSPC) for decades. However, the development of docetaxel chemotherapy and new androgen receptor-targeted agents, abiraterone acetate and prednisolone, apalutamide , enzalutamide and darolutamide (in combination with docetaxel chemotherapy) has proven that combination of treatments is more effective. Recently, intensification therapy, so-called "triplets", have emerged in the armamentarium of mHSPC treatment. Metastatic disease is a clinical state that remains poorly understood. The optimal diagnostic and management of patients with mHSPC are changing thanks to the development of new imaging techniques and therapies. The primary objective of this study is to develop and validate a predictive model for the occurrence of symptomatic progression, initiation of new treatments and death amongst patients with mHSPC treated with one of the approved treatment plans, on characteristics present at admission.

Newly identified adverse events of enzalutamide using the food and drug administration adverse event reporting system

ABSTRACT Objectives Enzalutamide, a second-generation anti-androgen drug, is an androgen receptor inhibitor developed to overcome resistance to first-generation anti-androgens, such as bicalutamide. This study aimed to identify previously undisclosed adverse events associated with enzalutamide. Methods Adverse reactions following enzalutamide administration were extracted from the Food and Drug Administration Adverse Event Reporting System (FAERS) database, and the data obtained were from 2014 to 2023. Four algorithms, namely ROR, PRR, BCPNN, and EBGM, were used to detect signs of adverse reactions associated with enzalutamide use. Results This study determined several adverse reactions in the nervous system, including hypogeusia, ageusia, dysgeusia, normal-pressure hydrocephalus, dementia, amnesia, balance disorders, and seizure-like phenomena. The mental aspects manifested as laziness, confusion, and eating disorders. Gastrointestinal system-related adverse reactions included dysphagia, constipation, fecal hardening, and abdominal discomfort. We identified several previously unreported adverse reactions, including normal-pressure hydrocephalus, dementia, balance disorders, eating disorders, and dysphagia. Conclusion Our study revealed novel adverse events associated with enzalutamide, particularly in the nervous system, that have not been previously documented. These findings have important implications for future clinical medication guidelines.

Prostate cancer public health system database from Brazil: Racial disparities and heterogeneity of treatment interventions to understand evidence-based practice patterns in a large real-world database.

5025 Background: The Brazilian Public National Health System (SUS) provides an opportunity to understand epidemiologic information, treatments, discrepancies in care, and costs of men with prostate cancer (PCa) using a large real-world dataset. This analysis focuses on racial disparities and heterogeneity of specific interventions to understand evidence-based practice patterns in Brazil. Additionally, the dataset can serve as a model for other low-middle income countries (LMIC). Methods: Patients included in the database were those with a diagnosis of PCa receiving care in the SUS from 01/01/2008 to 08/31/2022. Data were analyzed using a proprietary Healthcare Data Science platform offered by TECHTRIALS and included information regarding stage, demographics, cancer-related information, treatment-related information, and resources utilized. Results: 657,609 PCa pts were diagnosed and treated at SUS during the 14.5-year study period of whom 382,263 (58%) were brown/black (non-white) and 262,820 (42%) white. Median age of the population was 72.6 years, and did not vary with race. 26.16% of the pts were diagnosed with stage IV and this was not impacted by race or localization, including state or type of city (capital or not). Rates of radical prostatectomy and radiation utilization were similar between race categories. Additionally, in patients with stage IV disease, rates of systemic therapy utilization including chemotherapy with docetaxel (7.7%), with a tendency to increase use in the last years, and androgen receptor signaling inhibitors (ARSI) with (0.6%) or enzalutamide (0.08%), were low and similar between race categories. Rates of first-generation anti-androgens and estrogens were higher (56%) The total costs of prostate cancer directed care was R$4.31 billions (US$820 millions) and race did not impact total cost of care and cost by procedure or therapy type options. Conclusions: This is one of the largest studies using public health-system databases for Prostate cancer with Real World Data ever published. Race had no impact in presenting stage, treatment received and even in the costs involved. Underutilization of chemotherapy (docetaxel) in a scenario of limiting resources and without the use of new hormonal therapies is a matter of concern, together with an overuse of agents without proven survival advantage. Our data highlights the need for increased access to life prolonging agents for patients with metastatic PCa in the SUS.

Pretreatment Lymphocyte to C-Reactive Protein Ratio: An Independent Predictor of Overall Survival in Metastatic Hormone-Naïve Prostate Cancer Patients

IntroductionThe purpose of this study was to investigate the clinical value of combination of systematic inflammatory factors in predicting the outcomes of primary androgen deprivation therapy (ADT) plus first-generation antiandrogen treatment in metastatic hormone-naïve prostate cancer (mHNPC) patients. Materials and MethodsA total of 361 consecutive mHNPC patients from the discovery (n = 165) and validation (n = 196) cohorts were analyzed. All patients received primary ADT with surgical castration or pharmacologic castration accompanied by first-generation antiandrogens. We evaluated the prognostic impact of pretreatment lymphocyte to C-reactive protein ratio (LCR) on overall survival (OS) in both cohorts. ResultsThe median follow-up in the discovery and validation cohorts was 43.4 and 50.9 months, respectively. In the discovery cohort, low LCR (using an optimal cutoff threshold of 14,025) was significantly correlated with poor OS compared with high LCR (P < .001). Multivariate analysis revealed that the biopsy Gleason score and LCR were independent prognostic factors for OS. In the validation cohort, low LCR was also significantly correlated with poor OS compared with high LCR (P = .001). A multivariate analysis revealed that the extent of disease on bone scan grade, lactate dehydrogenase, and LCR were all independent predictors of OS. ConclusionsPretreatment low LCR is an independent predictor of poor OS in mHNPC patients. This may be informative in predicting the susceptible patients’ developing worse outcomes after being treated with primary ADT plus first-generation antiandrogen.

MP29-05 TREATMENT PATTERN AND HEALTH-RELATED QUALITY OF LIFE (HRQOL) OF PATIENTS (PTS) WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (MCRPC) IN THE UNITED STATES (US)

You have accessJournal of UrologyCME1 Apr 2023MP29-05 TREATMENT PATTERN AND HEALTH-RELATED QUALITY OF LIFE (HRQOL) OF PATIENTS (PTS) WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (MCRPC) IN THE UNITED STATES (US) Neal Shore, Lawrence Karsh, Daniel Shevrin, James Symanowski, Daniel Lin, Jeff Turner, David Russell, Yi Song, James Spalding, Filipa Negreiro, and David Penson Neal ShoreNeal Shore More articles by this author , Lawrence KarshLawrence Karsh More articles by this author , Daniel ShevrinDaniel Shevrin More articles by this author , James SymanowskiJames Symanowski More articles by this author , Daniel LinDaniel Lin More articles by this author , Jeff TurnerJeff Turner More articles by this author , David RussellDavid Russell More articles by this author , Yi SongYi Song More articles by this author , James SpaldingJames Spalding More articles by this author , Filipa NegreiroFilipa Negreiro More articles by this author , and David PensonDavid Penson More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003257.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Therapeutic advances in the management of mCRPC have given clinicians multiple treatment options and the potential for sequencing therapeutic agents, increasing the complexity of treatment decisions. This study aims to describe the treatment patterns and HRQoL of pts with mCRPC in the US from 2015 to 2021. METHODS: This prospective, observational, multicentre study (TRUMPET) enrolled male adult pts who initiated treatment for mCRPC from 147 urology and oncology sites in the US. The data from routine clinic visits and periodic HRQoL questionnaires were collected from Mar 2015 to Apr 2021. The study outcomes assessed patterns of care and HRQoL outcomes (Functional Assessment of Cancer Therapy-Prostate [FACT-P] and Brief Pain Inventory – Short Form [BPI-SF]) associated with mCRPC management. Descriptive analyses were used to evaluate results. RESULTS: Among the enrolled patients, the full analysis set included 832 patients with M1 mCRPC; the safety analysis set included 869 patients with M1 mCRPC. The median duration from initial diagnosis to baseline visit was 4.9 years, median initial prostate-specific antigen (PSA) level at diagnosis was 16.3 ng/mL, and mean (SD) Gleason score was 8.0 (1.18). Novel hormonal therapy (NHT) (enzalutamide and/or abiraterone) and immunotherapy were the most frequent initial treatments (Table). During the follow-up period, 43.8% (n=381) discontinued from the study before the first treatment switch, while 50.1% (n=435) switched treatment, with the majority of pts switching to NHT (n=280, 32.2%). At 1 year follow-up, cumulative first switches were 128 of 158 (81%) from immunotherapy to NHT, 41 of 88 (47%) switched from NHT to a different NHT, 11 of 17 (65%) switched from first-generation anti-androgens (AA) to NHT, 19 of 26 (73%) switched from chemotherapy to NHT, and 6 of 11 (55%) switched from radionuclide therapy to NHT. HRQoL measures showed similar trends (overlapping confidence intervals) of mean change from baseline across different first-line treatment options, irrespective of the initial treatment. CONCLUSIONS: NHT was the preferred first and second-line treatment option in pts with M1 mCRPC. HRQoL was similar regardless of initial treatment. Source of Funding: This study was funded by Astellas Pharma Inc. and Pfizer Inc., the co-developers of enzalutamide. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e382 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Neal Shore More articles by this author Lawrence Karsh More articles by this author Daniel Shevrin More articles by this author James Symanowski More articles by this author Daniel Lin More articles by this author Jeff Turner More articles by this author David Russell More articles by this author Yi Song More articles by this author James Spalding More articles by this author Filipa Negreiro More articles by this author David Penson More articles by this author Expand All Advertisement PDF downloadLoading ...

Real-world treatment patterns among veterans with nonmetastatic castration-resistant prostate cancer (nmCRPC).

e17042 Background: Prostate cancer (PC) is the most common cancer diagnosed among U.S. Veterans. Non-metastatic castration-resistant prostate cancer (nmCRPC) occurs in patients who, despite having received androgen deprivation therapy, experience a rising prostate-specific antigen (PSA) and castrate testosterone levels, with no evidence of metastatic disease on radiographic imaging. Given the recent approval of novel antiandrogens, the treatment landscape for nmCRPC has rapidly evolved. Although there have been numerous clinical trials examining the safety and efficacy of these treatments, few studies have identified real-world treatment patterns among nmCRPC patients. Methods: We conducted a retrospective observational study using patient information obtained from the Veterans Affairs (VA) Clinical Cancer Registry and the VA Corporate Data Warehouse (CDW) to identify patients who were diagnosed with PC at the VA, and later developed nmCRPC, defined as having: (1) evidence of rising PSA, i.e., 2 consecutive increases in PSA concentration over a baseline value; (2) evidence of ongoing androgen deprivation consisting of a serum testosterone level of ≤50 ng/dL (≤2.0 nmol/L); and (3) no evidence of metastatic disease on radiology reports. Treatments were extracted from CDW pharmacy dispensation records and were indexed at nmCRPC diagnosis. Results: A total of 12,549 patients were diagnosed with nmCRPC and treated in the VA from 2006 to 2020; of these, 7,239 (58%) were white, 3,386 (27%) were black, 784 (6%) were Hispanic, and 1,140 (9%) other. Median age at PC diagnosis was 69 years, with most patients residing in the South 4,817 (38%). Of the 7,659 (61%) patients receiving first-line (1L) nmCRPC therapy, 5,508 (72%) received bicalutamide, 621 (8%) ketoconazole, 563 (7%) abiraterone, 492 (6%) enzalutamide, and 242 (3%) flutamide. Although bicalutamide remained the most frequently used 1L nmCRPC therapy regardless of year, the adoption of abiraterone and enzalutamide beginning in 2012 resulted in a decline of 1L bicalutamide from 80% of patients in 2006 to 43% in 2020. Ketoconazole was the second most common 1L nmCRPC therapy and the most common second-line (2L) and third line (3L) nmCRPC therapy. Of patients receiving 1L therapy, 2,244 (31%) received 2L therapy, and of these, 708 (32%) received 3L therapy. Conclusions: To our knowledge, this is the largest real-world cohort of nmCRPC patients treated in a nationwide equal-access health care system. Despite the recent approval of several nmCRPC treatments (apalutamide, darolutamide, enzalutamide) which have demonstrated improved metastasis-free survival and treatment-related quality of life, our real-world findings suggest that older, first-generation antiandrogens remain the predominant 1L treatment for nmCRPC patients.

Multi-institutional Analysis of the Clinical and Genomic Characteristics of Black Patients with Metastatic Hormone-Sensitive Prostate Cancer.

BackgroundThe outcomes of metastatic hormone-sensitive prostate cancer (mHSPC) have significantly improved through treatment intensification, yet Black representation in those studies is suboptimal.MethodsA multi-institutional, retrospective analysis of Black men with mHSPC was conducted, focusing on baseline demographics, treatment patterns, genomic profiles, clinical outcomes including prostate-specific antigen response, time to castrate-resistant prostate cancer (CRPC), and subsequent treatments.ResultsA total of 107 patients, median age 64 years, 62% with de novo metastases at diagnosis and 64% with high-volume disease, were included. Twenty-nine patients (27%) were treated with androgen deprivation therapy (ADT) with and without first generation anti-androgens, while 20%, 38% and 5% received chemotherapy, abiraterone, and enzalutamide, respectively. At time of data cut-off, 57 (54%) patients had developed CRPC, with a median time to CRPC of 25.4 months (95% CI 20.3-30.4). The median time to CRPC was 46.3 months (18.9-73.7) and 23.4 months (18.6-28.2) for patients who received ADT with or without first-generation anti-androgens and treatment intensification, respectively. The 2-year survival rate was 93.3%, and estimated median overall survival of was 74.9 months (95% CI, 68.7-81.0). Most patients (90%) underwent germline testing; the most frequent known alterations were found within the DNA repair group of genes. Somatic testing revealed pathogenic alterations of interest, notably TP53 (24%) and CDK12 (12%).ConclusionIn our cohort, Black men with mHSPC presented with a high proportion of de novo metastases and high-volume disease. Treatment outcomes were very favorable with ADT-based regimens. The genomic landscape suggests different molecular profile relative to White patients with potential therapeutic implications.

Real-world use of first-generation antiandrogens: impact on patient outcomes and subsequent therapies in metastatic castration-resistant prostate cancer.

To investigate the recent real-world use of first-generation antiandrogens (FGAs) in metastatic castration-resistant prostate cancer (mCRPC) using a retrospective multicentre cohort study. The electronic CRPC Australian Database (ePAD) was interrogated to identify patients with mCRPC. Clinicopathological features, treatment and outcome data, stratified by FGA use, were retrieved and reported through descriptive statistics. Survival analyses were calculated using the Kaplan-Meier method and groups compared using log-rank tests. Factors influencing overall survival (OS) were analysed using Cox proportional hazards regression model. We identified 634 patients with mCRPC, enrolled in ePAD between January 2016 and March 2019, including 322 (51%) who received FGAs. The median follow-up was 21.9months. Patients treated with FGAs were more likely to have lower International Society of Urological Pathologists (ISUP) grade group (P=0.04), longer median time to CRPC (25.6 vs 16.0months, P<0.001), and were less likely to have visceral metastases (5.0% vs 11.2%, P=0.005) or to have received upfront docetaxel (P<0.001). A ≥50% reduction from pre-treatment prostate-specific antigen (PSA) level (PSA50 response) during FGA treatment occurred in 119 (37%) patients and was independently associated with improved OS (hazard ratio 0.233, P<0.001). Prior FGA treatment did not significantly influence the selection of subsequent life-prolonging treatments for mCRPC or their PSA50 response rates. In our present cohort, FGAs were commonly used in lower-risk mCRPC and their use did not significantly influence the choice or duration of subsequent systemic therapy. A PSA50 response to FGA therapy was an independent favourable prognostic marker associated with improved OS.

Real-world first-line (1L) treatment patterns in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) in a U.S. health insurance database.

5072 Background: Over the past 6 years, intensification of androgen deprivation therapy (ADT) with docetaxel (DOC) and novel hormonal therapies (NHT) [abiraterone, enzalutamide, and apalutamide], has been shown to improve survival outcomes in men with mCSPC. This study assessed the real-world utilization of effective combination therapies as 1L treatment in insured pts in the U.S. with mCSPC. Methods: This retrospective study used the Optum health insurance claims database, which includes pt claims data from both commercially insured and Medicare Advantage populations. Eligible pts were adult men with ≥1 claim with a metastatic International Classification of Diseases diagnostic code (first claim was index date) within 90 days (d) prior to, or any time after, a prostate cancer diagnosis between January 2014 and June 2019. Pts with evidence of systemic anticancer therapy during the 1-year pre-index baseline period were excluded, unless the first drug claim occurred within 90 d prior to the diagnosis of metastatic disease. The 1L treatments were identified as any treatment for mCSPC within 90 d pre-index, plus any other treatment received within 180 d of the first, and were grouped by regimen: ADT only; ADT + first-generation antiandrogens (AA); ADT + DOC; ADT + NHT; and ADT + NHT + DOC. Results: Of 4221 men with mCSPC, 2364 (56.0%) received ADT only; 892 (21.1%) ADT + AA; 577 (13.7%) ADT + NHT; 348 (8.2%) ADT + DOC; and 40 (0.9%) ADT + NHT + DOC. Pts who received ADT + DOC or ADT + DOC + NHT were generally younger than the other treatment groups (Table). By 2019, use of ADT only and ADT + AA had declined, while the use of ADT + NHT and ADT + NHT + DOC had increased (Table). However, in 2018 and 2019, the majority of men with mCSPC still received either ADT alone, or ADT + AA, including those with visceral metastases (Table). Survival analysis across treatment cohorts is ongoing. Conclusions: Despite level 1 evidence demonstrating improved survival with intensified treatment (ADT + DOC or NHT), this study shows its underutilization in pts with mCSPC. This is evident even in those with more aggressive disease (visceral metastases) as recently as 2019. These data highlight that a minority of pts with mCSPC received optimal life-prolonging therapies in a commercially insured and Medicare Advantage U.S. population. Further studies are needed to identify the reasons for this underutilization of intensified treatments.[Table: see text]

Prescribing patterns in patients with metastatic castrate-sensitive prostate cancer (mCSPC).

21 Background: Recent advances and approvals in mCSPC treatment offer improved outcomes. Docetaxel chemotherapy as well as novel hormonal therapies (NHT) including abiraterone, apalutamide and enzalumide are preferred regimens in addition to androgen deprivation therapy (ADT), with category 1 evidence supporting their use. Despite lack of consensus regarding use of first-generation anti-androgens (fgAI) aside from tumor flare prevention, they are still frequently prescribed. This multitude of options may lead to disparities in prescribing patterns. Methods: Retrospective analysis of pharmacy and medical claims data from the IQVIA database was performed. Patients were aged &gt;18 years and had an ICD 9/10 diagnosis of metastatic prostate cancer (PCa) with &gt;1 treatment claim. Patients on active therapy for another primary malignancy as well as those with &lt;12 months of data pre- and &lt;9 months post-first PCa-related event were excluded. Data was collected from 1/1/2015 to 6/30/2020. Treatment categories were classified as NHT, fgAI, chemotherapy, or ADT monotherapy. Results: National (N) and state of California (S) prescribing patterns are provided in Table. Nationally, Medicare reimbursed 16% NHT, 30% fgAI, 2% chemotherapy and 52% ADT, while third-party payers reimbursed 18% NHT, 20% fgAI, 3% chemotherapy and 59% ADT in 2020. State of California 2020 data yielded similar reimbursement patterns. In Southern California, academic centers prescribed 31% NHT, 23% fgAI and 46% ADT, while community-based practices prescribed 7% NHT, 36% fgAI and 57% ADT in 2020. In Southern California, community oncology practices prescribed 12% NHT, 40% fgAI, 2% chemotherapy and 44% ADT, while community urology practices prescribed 2% NHT, 38% fgAI, and 59% ADT in 2020. Data from 2015-2019 was similar. Conclusions: Although NHT utilization is increasing while chemotherapy utilization is declining, only a minority of mCSPC men received these therapies in 2020. Most of mCSPC men still receive ADT monotherapy or fgAI. Type of insurance carrier does not appear to affect prescribing patterns. Dramatic variations across treatment settings and different specialties exist, with academic centers prescribing more NHT than community-based practices and oncology practices prescribing more NHT than urology practices. These disparities should be addressed with provider education to standardize care delivery for mCSPC patients. [Table: see text]

PSA response to antiandrogen withdrawal: a systematic review and meta-analysis.

Antiandrogen withdrawal (AAW) response is the paradoxical decrease in prostate-specific antigen (PSA) following the withdrawal of antiandrogen in patients with advanced prostate cancer. Currently, the reported literature on the proportion of patients exhibiting AAW response and the differences in PSA response between the types of antiandrogens is unclear. This review aimed to explore the PSA response to AAW and to identify if the response depends on the type of antiandrogens. A literature search was performed using databases PubMed, Cochrane and EMBASE with a cut-off date of 23rd of November 2020. Studies reporting on outcomes of AAW and prostate cancer were included. Studies were screened by two reviewers and relevant data extracted. Meta-analysis of outcomes was reported using random-effects and fixed-effects model. A subgroup analysis was performed for type of antiandrogen. From 450 studies, 23 were included with a total of 1474 patients with advanced prostate cancer were available for further analysis. Overall, 395 (26%) patients had any reduction in PSA levels (95% CI: 20-32%) and 183 (11%) patients had a ≥50% reduction in PSA levels (95% CI: 6-16%). Among the 1212 patients on first-generation antiandrogens, 30% (95% CI: 23-38%) had any PSA decline with 15% patients having a ≥50% PSA decline (95% CI: 8-22%). In contrast, among the 108 patients on second-generation antiandrogens, 7% (95% CI: 0-13%) had any PSA decline and only 1% (95% CI: 0-5%) had a ≥50% PSA decline. Also, among the 154 patients on androgen synthesis inhibitors, 26% (95% CI: 19-33%) had any PSA decline and only 4% (95% CI: 0-13%) had a ≥50% PSA decline. One-fourth of patients treated with AAW show a PSA response. However, PSA response to AAW is uncommon with second-generation antiandrogens and androgen synthesis inhibitors. Further research is required to understand the differences in response between the types of antiandrogen.

Prognostic Factors in Hormone-sensitive Prostate Cancer Patients Treated With Combined Androgen Blockade: A Consecutive 15-year Study at a Single Japanese Institute.

There are several treatment options for metastatic hormone-sensitive prostate cancer (mHSPC) in the world. In recent years, the use of docetaxel, abiraterone, enzalutamide, and apalutamide has been used for mHSPC, but combined androgen blockade (CAB) therapy using first-generation antiandrogens has been widely used in Japan. There is a background. We performed a consecutive study of patients who received combined androgen blockade (CAB) at a single institute to determine the prognostic factors for mHSPC. We conducted a consecutive study of 237 mHSPC patients treated with CAB from 2003 to 2017 at the Gunma University Hospital. Prostate-specific antigen progression-free survival (PSA-PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. The associations between pre-treatment risk factors and the PSA response 3 months after starting CAB, PSA-PFS, and OS were evaluated by the Cox proportional hazards model. Among the 237 cases, the median PSA-PFS and OS times were 63.0 and 91.4 months, respectively. The median PSA-PFS and OS times of M1 cases (174 cases, 73.4% of all 237 cases) were 36.1 and 75.9 months, respectively. The Eastern Cooperative Oncology Group performance status (ECOG PS) score, hemoglobin (Hb), lactate dehydrogenase, extent of disease, visceral metastasis (no vs. yes), and PSA response after 3 months were significant predictors of OS according to Cox regression analysis of prognostic factors in M1 patients. The ECOG PS, Hb, visceral metastasis (no vs. yes), and PSA response after 3 months predicted OS high-risk patients in LATITUDE criteria. The OS was 92.1 months in the low-risk group (0-1 risk factors), 48.2 months in the intermediate-risk group (2 risk factors), and 16.9 months in the high-risk group (3-4 risk factors). CAB should be considered as a treatment option for strictly selected patients with mHSPC, even though novel treatments are available.

Second-Generation Antiandrogen Therapy Radiosensitizes Prostate Cancer Regardless of Castration State through Inhibition of DNA Double Strand Break Repair.

Simple SummaryThe combination of RT and the first generation AR blockers to improve the outcome in prostate cancer remain a matter of controversial debate in clinical trials. In the current study we aim to investigate the effect of three FDA approved second-generation antiandrogens (abiraterone acetate, apalutamide and enzalutamide), as more potent inhibitors of the AR signaling, on the cytotoxicity of RT in pre-clinical models. In vitro and ex vivo analyses revealed a strong radiosensitising effect for the second-generation antiandrogens, regardless of the castration state. The first-generation AR-blocker bicalutamide failed to show any radiosensitising effect. The radiosensitising effect of the second-generation antiandrogens was attributed to the inhibition of DSB repair. Together, we provide a proof-of-principle pre-clinical evidence to rationalize the clinical use of the second-generation antiandrogens to enhance the effect of IR as a potential strategy to improve the outcomes of PCa patients with localized disease who undergo ablative RT.(1) Background: The combination of the first-generation antiandrogens and radiotherapy (RT) has been studied extensively in the clinical setting of prostate cancer (PCa). Here, we evaluated the potential radiosensitizing effect of the second-generation antiandrogens abiraterone acetate, apalutamide and enzalutamide. (2) Methods: Cell proliferation and agarose-colony forming assay were used to measure the effect on survival. Double strand break repair efficiency was monitored using immunofluorescence staining of γH2AX/53BP1. (3) Results: We report retrospectively a minor benefit for PCa patients received first-generation androgen blockers and RT compared to patients treated with RT alone. Combining either of the second-generation antiandrogens and 2Gy suppressed cell growth and increased doubling time significantly more than 2Gy alone, in both hormone-responsive LNCaP and castration-resistant C4-2B cells. These findings were recapitulated in resistant sub-clones to (i) hormone ablation (LNCaP-abl), (ii) abiraterone acetate (LNCaP-abi), (iii) apalutamide (LNCaP-ARN509), (iv) enzalutamide (C4-2B-ENZA), and in castration-resistant 22-RV1 cells. This radiosensitization effect was not observable using the first-generation antiandrogen bicalutamide. Inhibition of DNA DSB repair was found to contribute to the radiosensitization effect of second-generation antiandrogens, as demonstrated by a significant increase in residual γH2AX and 53BP1 foci numbers at 24h post-IR. DSB repair inhibition was further demonstrated in 22 patient-derived tumor slice cultures treated with abiraterone acetate before ex-vivo irradiation with 2Gy. (4) Conclusion: Together, these data show that second-generation antiandrogens can enhance radiosensitivity in PCa through DSB repair inhibition, regardless of their hormonal status. Translated into clinical practice, our results may help to find additional strategies to improve the effectiveness of RT in localized PCa, paving the way for a clinical trial.

Tolerability of enzalutamide in prostate cancer: A meta-analysis.

e15629 Background: Enzalutamide, a second-generation androgen receptor inhibitor widely used in the treatment of prostate cancer, is often discontinued due to adverse events. A meta-analysis of randomized controlled trials was performed to examine the overall tolerability of enzalutamide in prostate cancer in comparison with controls. Methods: Databases including PubMed (up to December 2019) and Google scholar (up to December 2019) were searched to identify all phase II and III randomized controlled trials that compared enzalutamide with placebo (with or without other anti androgen drugs) along with reported data regarding drug discontinuation due to adverse events with enzalutamide and placebo. A random- or fixed-effects model was used to determine summary incidences, relative risks (RR), and 95% confidence intervals depending on the heterogeneity of included studies. Results: A total of 7 RCTs were eligible for analysis which included 7,343 patients (enzalutamide: n = 4116, control: n = 3227). The summary incidence of tolerability measured as discontinuation rate due to adverse events was 7.3% (95% CI: 6.1-8.7%) with enzalutamide and 5.7% (95% CI: 4.3-7.5%) with placebo or first-generation antiandrogens including bicalutamide, nilutamide or flutamide. The tolerability of enzalutamide varied with stage of prostate cancer with significantly higher incidence of discontinuation (9.8%, 95% CI: 8.0-11.9%) in non-metastatic prostate cancer group than metastatic prostate cancer group (6.7%, 95% CI: 5.8-7.6%). In comparison with controls, enzalutamide did not significantly affect the tolerability with an RR of 1.25 (95% CI: 0.95-1.66, P = 0.12). In addition, enzalutamide did not significantly affect the tolerability with an RR of 1.11 (95% CI: 0.80-1.53, P = 0.54) when compared to placebo. Conclusions: Enzalutamide may be comparable to placebo or first-generation antiandrogens in the tolerability for prostate cancer patients. Cautions should be taken to avoid unnecessary discontinuation.