Generation Antiandrogens Research Articles

Practical implications of androgen receptor inhibitors for prostate cancer treatment.

Antiandrogens have been used for the treatment of prostate cancer as a single agent or in combination with hormone deprivation therapy. New generation antiandrogens act like androgen receptor inhibitors (ARIs). Their binding complex blocks the pathways of cellular proliferation and differentiation of the prostate. Enzalutamide, apalutamide and darolutamide are the new ARIs that demonstrated acceptable tolerability and toxicity, both active in hormone-sensitive and castration-resistant prostate cancer (CRPC). There is no evidence of superiority of one drug over the other, therefore the therapeutic choice depends on the safety profile in relation to the individual patient, their comorbidities and clinical condition. ARIs have also shown promising results in association with new drugs that are active on patients with metastatic CRPC carrying the mutated breast cancer gene (BRCA). Before undergoing new antiandrogenic therapies, patients should be evaluated for cardiological and metabolic risk and possible drug interactions.

Abstract 4102: Treatment with androgen receptor targeting vaccines provides an overall survival benefit in AR-V7 expressing tumor models

Abstract Background: Androgen receptor (AR) signaling inhibition is part of the mechanism behind many effective prostate cancer therapies, including androgen deprivation and next generation anti-androgens. However in castration resistant prostate cancer up to 50% of treatment resistance has been linked to AR amplification or expression of the constitutively active RNA splice variant, AR-V7. Although the use of immune checkpoint blockade has failed to demonstrate clinical success, immunotherapeutic interventions remain attractive as prostate cancer’s relatively slow progression provides time for anti-tumor immune responses to develop. Cancer specific vaccines have the potential to enable and enhance tumor specific immune responses by stimulating and directing T cell immunity to important oncologic targets. We hypothesized that a cancer vaccine designed to induce a T cell response against cells expressing high levels of AR would result in an anti-tumor effect and potentially prevent or delay the development of therapeutic resistance. Methods: Adenoviral vaccines against AR (Ad-AR) or AR splice variant 7 (Ad-AR-V7) were used to evaluate the potential of AR targeting vaccination in mouse models. We evaluated AR and AR variant specific adaptive responses produced by our vaccines with naïve and tumor-bearing mice by ex vivo peptide restimulation. We challenged vaccinated mice with multiple syngeneic subcutaneous tumor models that we engineered to express AR-V7, including a PTEN-/- p53-/- prostate tumor cell line. Finally we tested our vaccines in a therapeutic regimen, vaccinating mice after implanting our subcutaneous AR-V7 expressing models. Results: Across multiple strains of mice, AR or AR-V7 targeting adenoviral vaccination induced robust adaptive immune responses against the N-terminal domain of AR. Vaccination with either Ad-AR or Ad-AR-V7 resulted in significant anti-tumor responses, providing a significant overall survival benefit and complete tumor rejection by the majority of mice vaccinated against AR or AR-V7. Similarly tumor bearing mice treated with Ad-AR or Ad-AR-V7 vaccination displayed tumor growth inhibition or complete tumor regression resulting in an overall survival benefit. Additionally, we found that vaccine responses were unaffected by the use of the approved antiandrogen drug enzalutamide, suggesting that vaccinations could be deployed in tandem with standard-of-care therapies. Conclusions: Vaccination against AR and AR splice variants can induce AR specific adaptive immune responses capable of inhibiting the growth of AR-V7 expressing tumor models, illustrating the potential of AR and its splice variants as immunologic targets in prostate cancer. Citation Format: Robert D. Marek, Junping Wei, Tao Wang, Xiao-Yi Yang, Gangjun Lei, Zachary C. Hartman. Treatment with androgen receptor targeting vaccines provides an overall survival benefit in AR-V7 expressing tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4102.

Effectiveness and safety of darolutamide as a component of combination therapy in patients with prostate cancer

Prostate cancer is an extremely important problem in current urologic oncology. For a long time, the golden standard of treatment of common forms of prostate cancer at the stage of distant metastases was androgen deprivation therapy directed at suppression of native testosterone level. Combination treatment using long-term androgen deprivation therapy and new generation antiandrogens is currently a scientifically substantiated conceptually new standard of therapy which has replaced treatment paradigm using androgen deprivation therapy as a monotherapy in patients with metastatic hormone-sensitive prostate cancer. The article presents the results of large trials performed in patients with metastatic hormone-sensitive prostate cancer and characterizes the role of one of the most effective and safe drugs, darolutamide, used to treat patients of this subgroup.

Transcriptomic Analysis to Uncover the Mechanism of Radiosensitization of AR-Positive Triple Negative Breast Cancers with AR Inhibition

The androgen receptor (AR) has been shown to drive tumor growth in triple negative breast cancers (TNBC), and previous work demonstrated AR inhibition as a strategy for radiosensitization in AR-positive (AR+) TNBC. Despite its role in radioresistance, the mechanistic role of AR in response to radiation therapy (RT) remains unknown, as does the benefit of 2nd generation anti-androgens in this context. We hypothesized that all 2nd generation anti-AR therapy would radiosensitize similarly and that canonical AR transcriptional function was responsible for radioresistance in these models. Radiosensitization was assessed using 2nd generation AR antagonists (apalutamide, enzalutamide, and darolutamide) using clonogenic survival assays in MDA-MB-453, SUM185, MFM-223, and MDA-MB-231 cells at 2-6Gy. Cellular fractionation experiments were performed and quantitated to determine the location of the AR protein in cells treated with AR agonists +/- RT. RNA Seq was performed and transcriptomic approaches were used (Advaita iPathway analysis) to investigate AR-mediated effects in response to RT. Inhibition with the 2nd generation anti-androgens enzalutamide and apalutamide is sufficient to radiosensitize AR+ TNBC models (rER: 1.34-1.41); while darolutamide had no effect on radiosensitivity (rER: 0.96-1.11). Additionally, TNBC cells with low AR expression were not radiosensitized by AR inhibition with any drug (rER: 0.96-1.03). While stimulation with the synthetic androgen methyltrienolone R1881 is sufficient to induce nuclear translocation of AR in AR+ TNBC cells, AR inhibition with enzalutamide, apalutamide, or darolutamide blocked AR nuclear translocation under growth conditions with charcoal stripped serum or fetal bovine serum. When cells are treated with R1881+RT, nuclear translocation of AR was induced at similar or greater levels compared to R1881 alone in AR+ TNBC cells. Combination treatment of RT with enzalutamide in the presence of hormones reduced nuclear localization of AR (32-39% reduction) compared to RT alone. RNA-sequencing after RT identified transcriptional changes potentially regulated by AR+RT, including changes in the NHEJ pathway genes. Additionally, pathway analyses in these models demonstrated changes in the MAPK/ERK signaling pathway, among others, that may regulate RT resistance in AR+ TNBC models. Most 2nd generation anti-androgens confer radiosensitization in AR+ TNBC models with cellular localization changes of AR noted after RT. The known structural differences amongst 2nd generation anti-androgens may account for differences in radiosensitization noted. Furthermore, AR-mediated radioresistance may be due, at least in part, to downstream MAPK/ERK signaling. This work builds on the mechanistic understanding of AR-mediated radioresistance in AR+ TNBC and may expose vulnerabilities to overcome resistance to combination treatment with AR inhibition and RT.

Clinical aspects of prostate cancer in patients with germinal and somatic mutations in DNA homologous recombination repair genes

Background. In clinical practice, there is a need to predict clinical behavior of prostate cancer with germinal and somatic mutations in DNA homologous recombination repair (HRR) genes due to an atypical response to standard treatment methods. Also, the expediency of testing the mutational status of HRR genes is dictated by the possibility of using the PARP-inhibition strategy in metastatic castration-resistant prostate cancer (mCRPC). In addition to expanding the possibilities for targeted therapy the necessity to inform the relatives of mutation carriers is underestimated. It is also important to realize the fact of accumulation of somatic changes both in the primary tumor and in the metastatic lesion during tumor evolution and under treatment, which dictates the possibility of repeated biopsy with exhausted therapy possibilities.Aim. Evaluation of prostate cancer clinical behavior features and response to drug therapy depending on the identified mutations in the HRR genes.Materials and methods. The study was performed at the Clinical Oncological Dispensary No. 1 (Krasnodar). Clinical and morphological data of 27 patients with prostate cancer and identified germinal and somatic mutations in HRR genes (BRCA1, BRCA2, ATM, BARD, BRIP1, CDK12, CHEK1, CHEK2, PALB2, RAD51B, RAD51C, RAD54L, FANCL) were retrospectively analyzed. Statistical analysis was performed using the IBM SPSS Statistics v.22 statistical package.Results and conclusion. The median age of patients was 61 years. The most frequent were mutations in the BRCA2 (37 %), CHEK2 (18.5 %), ATM (14.8 %) genes. More than half of the patients (69 %) had primary metastatic disease. The differentiation grade of G2 and G3 according to the classification of the International Society of Urological Pathologists (ISUP) with Gleason score of 7 (3 + 4) and 7 (4 + 3) were both detected in 27 % of cases. The type of mutation did not affect the time of castration resistance development (p = 0.216). The time to castration resistance increased close to statistical significance in the case of primary stage of T3–4N0M0 compared to other stages (log-rank p = 0.092). Progression-free survival (PFS) with docetaxel monochemotherapy was significantly longer when prescribed for metastatic hormone-sensitive prostate cancer with mutations in HRR genes compared to mCRPC (p = 0.061) and to primary metastatic disease (p = 0.04). At the same time, the risk of progression during therapy was higher for presence of regional lymph node metastases with primary advancement (p = 0.005; hazard ratio 1.167; 95 % confidence interval 2.765–267). There was also an advantage in PFS when prescribing docetaxel for BRCA1/2 and ATM mutations in comparison with other mutations (p = 0.038). When prescribing therapy with 2nd generation antiandrogens or abiraterone, progression-free survival is higher in the group of patients with prostate cancer with Gleason score of 7 (4 + 3) compared to cohort with other morphological types, and this difference is almost statistically significant (log-rank p = 0.091, Breslow p = 0.076, Taron-Ware p = 0.074). Targeted therapy with the PARP inhibitor Olaparib in the performed trial was received by 10 patients with HRR mutations. At the same time, according to the data of the PROfound trial, the advantage of Olaparib in radiological PFS was shown in germinal and somatic mutations in group A (BRCA1, BRCA2, ATM) and in the general group (A and B – other HRR mutations).

Androgen receptor signaling mechanism in prostate cancer: resistance to antiandrogen therapy and association with DNA repair genes

Background. Metastatic castration-resistant prostate cancer remains a complex problem due to patients' previous treatments and limited selection of subsequent therapies. While 2nd generation antiandrogens are initially effective, resistance to them is not an exceptional event. Mechanisms depending on androgen receptor and independent of it have been described. A special focus is on mutations in DNA repair genes, particularly genes involved in homologous recombination repair (HRR) as a possible cause of somatic genetic abnormalities specifically in progressive metastatic disease. However, data on the effect of the HRR defect on the effectiveness of antiandrogen therapy for prostate cancer are very limited, which requires additional clinical studies.Aim. To evaluate the effect of clinical, morphological, molecular and genetic factors on the effectiveness of enzalutamide antiandrogen therapy in patients with prostate cancer and known mutations in DNA repair genes involved in HRR and mismatch repair.Materials and methods. The study was performed at the Clinical Oncological Dispensary No. 1 (Krasnodar). Retrospective analysis of clinical and morphological parameters of 54 patients with prostate cancer who received enzalutamide antiandrogen therapy and with known status of germ line and somatic mutations of HRR DNA repair genes (BRCA1, BRCA2, ATM, BARD, BRIP1, CDK12, CHEK1, CHEK2, PALB2, RAD51B, RAD51C, RAD54L, FANCL) and microsatellite instability in immunohistochemical determination of mismatch repair deficit was performed. Statistical analysis was performed using IBM SPSS Statistics v.22 software.Results and conclusion. In 17 of 54 patients, pathogenic germline and somatic mutations of HRR genes were detected: 7 mutations in BRCA2 gene, 4 - in CHEK2, 2 - in BRCA1, 2 - in CDK12, 1 - in BRIP1 and 1 - in ATM. It was shown that in the group of patients with metastatic castration-resistant prostate cancer, histological grade per the International Society of Urological Pathology (ISUP) G2 (total Gleason score 7 (3 + 4)) is significantly associated with the absence of HRR mutation, and grade G3 (total Gleason score 7 (4 + 3)) was associated with HRR mutations (р <0.05). Increase in prostate-specific antigen (PSA) level/biochemical progression 12-16 weeks after enzalutamide therapy start was significantly associated with metastatic castration-resistant prostate cancer without HRR mutations (р <0.05). In case of tumor response to enzalutamide therapy, decrease in PSA level did not depend on the age of disease onset, differentiation grade, primary advancement, previous docetaxel treatment, and presence of HRR mutation. Cox multivariate regression test showed that prescription of docetaxel before enzalutamide increased the risk of PSA-progression (hazard ratio (HR) 5.160; 95 % confidence interval (CI) 1.549-17.189; р = 0.008) and radiographic progression (HR 5.161; 95 % CI 1.550-17.187; р = 0.008). Progression risk decreased with increased level of PSA decrease 12-16 weeks after enzalutamide therapy start: for PSA decrease >30 % HR 0.150; 95 % CI 0.040-0.570; р = 0.005; for PSA decrease >50 % HR 0.039; 95 % CI 0.006-0.280; р = 0.001; for PSA decrease >90 % HR 0.116; 95 % CI 0.036-0.375; р = 0.000. Presence of HRR mutation, age <58 years, primary metastatic disease and poorly differentiated morphology did not affect duration without PSA-progression (p >0.05). Kaplan-Meier curves showed a trend towards increased time to development of castration resistance in the group of primary early cancer (Breslow р = 0.06; Tarone-Ware р = 0.062). Subgroup analysis showed that in the cohort of patients with castration-resistant prostate cancer (n = 48), absence of HRR mutation in patients who previously received docetaxel therapy increases time to PSA-progression compared to patients with mutations (log-rank р <0.05).

Abstract 3891: Epigenetic rewiring promotes antiandrogen resistance and metastasis via heterogenous oncogenic drivers in prostate cancer

Abstract Prostate cancer (PCa) is the most diagnosed cancer among American men, which has traditionally been treated through hormone therapy. However, after hormone therapy many patients with PCa still develop a more aggressive stage of PCa, called metastasis castration resistant prostate cancer (mCRPC). The second- generation antiandrogens, such as enzalutamide or apalutamide, are used to competitively inhibit the androgen receptor (AR) signaling and achieved great clinical success. However, most of the mCRPC patients would develop resistance to the targeted therapy drugs within 6 months to 2 years after initial administration. Consequently, understanding the molecular mechanism of antiandrogen resistance, has become a critical endeavor to provide a greater benefit to patients. mCRPC is characterized by extensive heterogeneity of genomic copy number alterations, which may lead to antiandrogen resistance. TP53 and RB1 alterations have been reported to be dramatically enriched in mCRPC neuroendocrine cancer and we have previously found that inactivation of both TP53 and RB1 confers resistance to antiandrogen through lineage plasticity, where cancer cells can transdifferentiate from a luminal lineage to a mixture of basal and neuroendocrine lineages, which is no longer dependent on AR signaling. Despite these exciting discoveries, only 10% of patients have TP53 and RB1 loss and it is estimated that approximately 40% of patients develop antiandrogen resistance through an undiscovered mechanism.To identify more genomic alterations which confer antiandrogen resistance, we performed an in vivo library screening and identified some of the frequently depleted genes as top candidates mediating antiandrogen response, including the chromatin helicase DNA-binding factor (CHD1). Strikingly, the loss of CHD1 establishes an altered chromatin landscape and enables the activation of heterogenous resistant subclones to emerge, including clones with ectopic NR3C1/GR, POU3F2/BRN2, TBX2, and NR2F1. This work provided an innovative model to explain the dramatically increased tumor heterogeneity in therapy resistant prostate cancer and suggested potential druggable targets to overcome resistance. Building on those exciting results, we are now examining the underlying mechanism how the epigenetic rewiring in resistant tumor clones confer resistance and monitoring the evolution of those heterogenous resistant subclones. Furthermore, we are revealing the collaborative function of those four resistant driver genes in promoting metastasis to various distal organs through multidisplinary approaches including single cell transcriptomics and 3D organoid modeling. The completion of this study will not only add clarity to the mechanism of antiandrogen resistance but may also lead to the development of novel biomarker and therapeutic approaches to overcome resistance. Citation Format: Xiaong li, Su Deng, Julisa Gonzalez, Carla Rodriguez Tirado, Choushi Wang, Nickolas A. Johnson, Lauren Metang, Ping Mu. Epigenetic rewiring promotes antiandrogen resistance and metastasis via heterogenous oncogenic drivers in prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3891.

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

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

Underutilization of best systemic therapy in patients with metastatic prostate cancer.

111 Background: Advancement of treatment pathways in the management of metastatic prostate cancer (mPC) has identified newer systemic agents associated with survival advantage over androgen deprivation therapy (ADT) alone. Despite FDA approvals and guideline recommendations outlining standard of care (SOC) intensification of (ADT) with such additional systemic therapies such as docetaxel or novel hormonal therapies (NHT), these treatments are not being utilized uniformly by all practitioners. Our objective is to assess the utilization of such advanced therapies in patients with mPC and study differences in prescribing patterns. Methods: Between 2017 to present, we retrospectively identified all consecutive men with prostate cancer in a single health system. Electronic health record ICD code inquiries were used to identify patients. The population was further restricted utilizing diagnosis codes to include only those with metastatic prostate cancer and to exclude patients with second primary cancers. All treatment modalities and demographic information were analyzed to assess for prescribing patterns. Results: In total, 5,761 men had a diagnosis of prostate cancer. Exclusion criteria applied stepwise removed those with age <18 years (2 patients) and secondary malignancies (1046 patients), resulting in 4,713 men for analysis. Of these, 665 men were found to have mPC and included in the final cohort. Mean patient age was 70.3 ± 9.6 years. We found no statistically significant difference in SOC prescribing pattern based on race, ethnicity, insurance type, zip code, 2020 United States census household median income, nor year of treatment. There was, however, overall low utilization of intensification of ADT with docetaxel or NHT at 42%, with 58% of patients still being treated with only first generation antiandrogens or luteinizing hormone releasing hormone agonists. Conclusions: In a large health system, we found that next generation care can be provided independent of insurance payor profile, race, ethnicity, and socioeconomic status. However, despite guidelines to support newer systemic agents for patients with mPC, we continue to observe that it is underused in clinical practice. Additional studies are needed to identify potential clinician and patient barriers, as well as prescribing pattern failures that are limiting the implementation of evidence-based treatment beneficial to overall survival.

Determinants of Mortality among Patients Managed for Prostate Cancer: Experience from Korle Bu Teaching Hospital in Ghana.

Over the past two decades, diagnosis and treatment approaches for men with prostate cancer have changed dramatically, with improvements in established prostate cancer treatments and new treatment strategies. However, In sub-Saharan African countries, there is a paucity of data on the characteristics and treatment of men who eventually die from Prostate Cancer (PCa). We used the clinical records of patients who died from PCa to describe the natural history and treatment PCa patients in Ghana. From 2013 to 2022, the medical records of 234 men who died of PCa at a tertiary hospital in Ghana were prospectively collected and retrospectively analysed. The mean age at death was 71.6 years, and the median was 72.5 years. 51.3% died within 24 months of diagnosis, 23.0% between 2 and 5 years after diagnosis, and a quarter survived for more than 5 years. Over 80% presented with advanced disease, characterised by high prostate-specific antigen (PSA) levels, a high T stage on DRE, and evidence of metastasis. 43.6% presented with haemoglobin levels below 10ng/dl at diagnosis. These patients had the worst outcome, with 73% dying less than 2 years after diagnosis. The 5-yr survival rate of patients who presented with metastatic disease was 21.2 %. Over 80% were treated with bilateral total orchidectomy, with less than 10% receiving treatment intensification with the newer generation antiandrogens or chemotherapy. Our analysis shows that patients who die from PCa have aggressive disease, are diagnosed at an advanced stage, and are relatively younger than in Western countries. There is also a slow uptake of newer treatment strategies for metastatic prostate cancer. These results confirm literature suggesting that blacks have poorer outcomes due to the disease's aggressive nature. Further research is needed to understand the mechanisms and also define appropriate management for metastatic PCa in sub-Saharan Africa.

Second generation anti-androgens and androgen deprivation therapy with radiation therapy in the definitive management of high-risk prostate cancer.

Evolving data suggest that men with high-risk localized prostate cancer may benefit from more potent androgen receptor inhibition in the context of curative intent radiotherapy. Recently updated American Society for Clinical Oncology (ASCO) evidence-based guidelines and the National Comprehensive Cancer Network (NCCN) Guidelines have updated recommendations for the consideration of adding second generation anti-androgens to androgen deprivation therapy (ADT) in men receiving radiation therapy (RT) for noncastrate locally advanced high and very high risk nonmetastatic or node positive prostate cancer. We conducted a comprehensive review of existing published and abstract presented evidence behind RT with ADT for the definitive management of high-risk prostate cancer, particularly focused on the current phase II and III trial evidence for the addition of second generation anti-androgens to ADT in definitive RT treatment of high-risk prostate cancer and specifically focused on the recent STAMPEDE trial results with abiraterone acetate. We review the biological mechanisms in which second generation anti-androgens may help mitigate ADT resistance and provide radiosensitization through inhibition of DNA repair. Finally, we discuss ongoing clinical trials of potent androgen receptor (AR) inhibitors with ADT in this non-metastatic high-risk radiotherapy setting that may inform on future treatment guidelines. Recent data suggest an overall survival benefit as well as increased probabilities of disease free and metastasis free survival in men with high and very high-risk localized, node positive, and oligometastatic hormone sensitive prostate cancer with abiraterone acetate and prednisone and support the use of potent AR inhibitors in this setting after informed decision making.

Clinical surveillance and PSA outcomes among patients with non-metastatic castration resistant prostate cancer (nmCRPC) treated with a next-generation androgen receptor inhibitor (ARI) in urology clinics with or without in-office dispensing (IOD).

410 Background: As use of oral therapies in prostate cancer treatment increases, IOD of oral medication has become more common. The objective of this study was to describe clinical surveillance practices and PSA outcomes in nmCRPC patients (pts) treated in clinics with or without IOD. Methods: nmCRPC pts with ≥1 ARI prescription (Rx) were identified in data from 95 US urology practices between 2018-2021. Pts were categorized into 3 groups: (1) Treated in IOD clinic and received ARI onsite within 14 days of Rx (IOD+), (2) Treated in IOD clinic but no onsite ARI receipt within 14 days of Rx (IOD-), and (3) Treated in a clinic without IOD (non-IOD). Descriptive analyses were conducted on pt characteristics, PSA and imaging data. PSA response, reported using Kaplan-Meier rates, was defined as ≥50% reduction in post-index (PI; index date = 14 days after 1st ARI Rx) PSA compared to baseline PSA (measured within 13 weeks before 1st ARI prescription). PSA progression was defined as ≥25% increase in PI PSA above baseline PSA. Results: 3,300 nmCRPC pts were identified (N = 615 IOD+; 2,474 IOD-; 211 non-IOD). Baseline characteristics differed for race, use of bone resorption agents and 1st generation anti-androgens, and PSA doubling time (PSADT; table). By 6 months PI, PSA screening was observed in similar proportions of pts in IOD and non-IOD, while PSA response was observed in a higher proportion of IOD+ (80%) than IOD- (64%) or non-IOD (63%). PSA progression was observed in fewer IOD+ pts (10%) than IOD- (16%) or non-IOD (17%). PI imaging was conducted in similar proportions of pts in IOD and non-IOD clinics; however, non-IOD performed more imaging per pt and time to imaging was shorter than in IOD+ clinics. Conclusions: Differences were noted in patient characteristics and prior medication use in ARI-treated patients within IOD and non-IOD clinics. IOD+ was observed to have higher rates of PSA response, fewer patients with PSA progression, and use fewer imaging tests after ARI initiation than non-IOD or IOD-. Additional studies controlling for differences in baseline characteristics and examining longer term outcomes are needed to understand how IOD services impact quality of patient care.[Table: see text]

Radiographic paradoxical response in metastatic castrate-resistant prostate cancer (mCRPC) managed with new generation anti-androgens: a retrospective analysis.

Prostatic specific antigen (PSA) has well-recognized limitations as a marker for treatment response and disease progression. Post hoc analysis of the PREVAIL trial reported 24.5% of chemotherapy naïve metastatic castration-resistant prostate cancer (mCRPC) patients on enzalutamide had radiographic progression on conventional imaging with nonrising PSA. In this study, we sought to study the discordance of imaging with PSA kinetics in mCRPC patients on second generation anti-androgens (SGA)post-chemotherapy using combined conventional imaging, and new generation imaging in the form of C-11 choline positron emission tomography/computed tomography (C[11] choline PET/CT) scan. We retrospectively reviewed the medical records of 123 patients with mCRPC treated with SGA (Abiraterone or Enzalutamide) after docetaxel between 2016 and 2019. Patients underwent PSA testing, and C[11] choline PET/CT scan at baseline level before starting treatment with SGA, then every 3-6 months as part of their follow up evaluation. Loss of response to SGA was defined by increase in corrected maximum standardized uptake value (SUVmax) of pretreatment lesions on C-11 Choline PET/CT, and/or development of new lesions. Suspicious new lesions were confirmed by biopsy and/or conventional imaging. We identified 123 mCRPC patients who received SGA (Abiraterone, n = 106; Enzalutamide, n = 17) after docetaxel. Median duration of therapy was 13.9 months (interquartile range: 8.75-21.14). Approximately 43% (n = 53) of subjects in this study exhibited an increase in choline avidity while on SGA. Of this group, 60.4% of patients experienced a parallel rise in PSA (Group-A), whereas 39.6% displayed a paradoxical response (PR) (Group-B), defined as increased choline avidity combined with stable or down-trending PSA. Median PSA at time of increase in choline avidity was 3.1 ng/ml for Group-A, and 1.3 ng/ml for Group-B (p = 0.0176). Median SUVmax was similar in both groups (4.9 for Group-A, 4.6 for Group-B; p = 0.6072). The median time for increase in choline avidity was 9.5 versus 3.9 months for Group-A versus Group-B, respectively (Log-Rank = 0.0063). Nearly 40% of mCRPC patients placed on SGA post docetaxel chemotherapy will exhibit paradoxical responses to therapy, therefore, warranting close follow up with imaging. C-11 choline PET/CT imaging is a useful tool that can help in early predication of disease progression or treatment failure.

An observational multicenter study to evaluate the efficacy and safety of degarelix® for prostate cancer in routine clinical practice

Background. Prostate cancer (PCa) is an actual disease and a frequent oncological pathology in men. The main methods of radical treatment of patients with PCa are radical prostatectomy and radiation therapy. Radical prostatectomy s the most commonly used method of therapy in patients with localized PCa. Adjuvant hormone therapy after surgical treatment is the standard method of therapy in patients with the presence of lymph node metastases. At the same time, the standard approach of treatment of patients with metastatic PCa is combination therapy with medical (using of analogues or antagonists of luteinizing hormone-releasing hormone (LHRH) or surgical castration in combination with chemotherapy with docetaxel or new generation antiandrogens (enzalutamide or apalutamide)). Numerous studies have demonstrated the importance of achieving minimum testosterone levels at all stages of drug therapy in patients with PCa. It has also been shown that the use of LHRH analogues may be less effective to the use of LHRH antagonists (degarelix) in relation to the effectiveness of testosterone suppression. Thus, conducting a study aimed at studying the effectiveness of testosterone suppression using LHRH antagonists in various clinical situations and patient populations in real clinical practice is a very actual task.Aim. To evaluate the effectiveness and safety of castration therapy using degarelix in real clinical practice and in various clinical situations.Materials and methods. The object of an observational non-interventional study was 132 patients with PCa from 13 cancer centers of Russian Federation who were treated with LHRH antagonist degarelix. The study was non-interventional (observational), retrospectively-prospective, open multicenter and not randomized. In accordance with the design of the study, depending on the clinical situation, patients were divided into 3 groups: group A (n = 52; 39.4 %) – patients with primary metastatic hormone-sensitive PCa, who were shown to undergo combined drug treatment with castration therapy as one of the components; group B (n = 43; 32.6 %) – patients, who underwent combined hormonal and radiation treatment (ADT + radiation therapy); group C (n = 37; 28 %) – patients who underwent surgical treatment (radical prostatectomy with extended PLND) with the presence of metastases in the lymph nodes identified by the results of a morphological examination (pN1).Results and conclusion. As a result of a non-interventional observational study, high efficacy of androgen-deprivation therapy with the use of degarelix was demonstrated in relation to the suppression of testosterone and PSA in patients with primary metastatic and locally advanced PCa in various clinical situations, as well as low toxicity and satisfactory tolerability of this variant of hormonal treatment.

Understanding the Current Therapeutic Landscape for Advanced Prostate Cancer (CME article)

Treatment of advanced prostate cancer has improved rapidly in the past two decades with the introduction of many new therapeutics including several entirely new therapeutic classes. Whereas androgen deprivation therapy was previously the first and only line of treatment available, modern therapy also routinely employs second generation anti-androgens, chemotherapy, immunotherapy, radiopharmaceuticals, bone modifying agents, and poly(ADP-ribose) polymerase (PARP) inhibitors, with a resulting substantial increase in patient survival. This review aims to summarize the current treatment landscape for advanced prostate cancer, with a particular focus on hormone refractory (also known as ‘castration resistant’) prostate cancer (HRPC), and we hope will serve as a practical guide for clinicians and trainees.

Abstract 5282: Preclinical efficacy of abiraterone plus capivasertib in mouse Pten-deficient prostate cancer

Abstract Prostate tumors are characterized with constitutively activated AKT signaling primarily through the loss of PTEN. Second generation antiandrogens such as abiraterone acetate have improved the survival of prostate cancer patients, however, resistance remains a problem and patients with PTEN-deficient tumors have poorer outcomes to abiraterone treatments. Moreover, PTEN-deficient tumors are also characterized with immunosuppressive tumor microenvironments. In this study we investigate the benefit of adding capivasertib, a potent pan-Akt inhibitor, to abiraterone therapy in a preclinical model of Pten-deficient prostate cancer and examine the antitumor efficacy and its influence on antitumor immunity. The temporal effects of abiraterone and capivasertib alone and as combination therapy were evaluated after one and four weeks of dosing in conditional transgenic mice harboring Pten-deficient prostate tumors. While abiraterone therapy alone reduced genitourinary tract weights, which contain both AR-sensitive normal accessory sex organs and prostate tumor, the treatment had no overall effect on prostate tumor burden. Mice treated with capivasertib monotherapy experienced tumor burden reductions of 8.2% and 15.6% at week 1 and 8, respectively, moreover, the treatment combination of abiraterone + capivasertib significantly improved the therapeutic effect with tumor burden reductions of 35.6% and 37.8% at weeks 1 and 4, respectively versus vehicle control. qRT-PCR analysis of Ar target genes showed decreased expression in mice treated with abiraterone. All treatment combinations showed increased gene expression levels of Casp3 in tumors from mice at week one but were greatest in those treated with abiraterone alone or in combination and increased expression levels were sustained only in the combination cohort at week four. Immunological profiling of tumors from mice treated with abiraterone + capivasertib using qRT-PCR-based panel of immune-related genes revealed enrichments in genes associated with phagocytosis, antigen processing and dendritic cell function. Examination of the tumor draining lymph nodes by flow cytometric analysis showed ~1.5-fold-increases in the abundance of migratory dendritic cells (CD11b+\CD11c+\XCR1+) in all pharmacologically treated mice (versus vehicle control) and remained elevated only in mice receiving capivasertib as monotherapy or combination at week four. Additionally, mice treated with combination therapy also had enrichments in genes sets associated to T cell, NK cell and as well as T cell activation, cytotoxicity, and interferon gamma signature. The findings from this study provide preclinical evidence for the efficacy of combination therapy with abiraterone plus capivasertib and provides insights into its immunomodulatory effects and influence on antitumor immunity. Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Keiko Kuroka, Kazutoshi Fujita, Eri Banno, Kazuko Sakai, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura. Preclinical efficacy of abiraterone plus capivasertib in mouse Pten-deficient prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5282.

MP27-18 PRACTICE PATTERNS IN MANAGEMENT OF HORMONE SENSITIVE METASTATIC AND CASTRATE-RESISTANT NON-METASTATIC PROSTATE CANCER

You have accessJournal of UrologyCME1 May 2022MP27-18 PRACTICE PATTERNS IN MANAGEMENT OF HORMONE SENSITIVE METASTATIC AND CASTRATE-RESISTANT NON-METASTATIC PROSTATE CANCER Daniel D. Joyce, Vidit Sharma, Andrew Zganjar, Eugene D. Kwon, and R. Jeffrey Karnes Daniel D. JoyceDaniel D. Joyce More articles by this author , Vidit SharmaVidit Sharma More articles by this author , Andrew ZganjarAndrew Zganjar More articles by this author , Eugene D. KwonEugene D. Kwon More articles by this author , and R. Jeffrey KarnesR. Jeffrey Karnes More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002570.18AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The treatment landscape for hormone sensitive metastatic (mHSPC) and non-metastatic castrate-resistant prostate cancer (nmCRPC) has evolved to include multiple options with similar oncologic benefit and no clear guideline consensus on sequencing of these agents. Real-world treatment patterns in this space are largely unknown. Our primary objective was to describe contemporary prescribing trends among oncologists and urologists managing HSPC and nmCRPC. METHODS: Using the IQVIA claims-based dataset, which includes over 17 million cancer patients and 10,000 providers across all 50 United States, we identified all men age 18 and older who received systemic treatment for mHSPC or nmCRPC between 2015 and 2021. Treatments were divided into 4 groups: novel hormonal (NHT: apalutamide, enzalutamide, darolutamide, abiraterone), 1st generation anti-androgens (AA, such as bicalutamide), LHRH monotherapy, and chemotherapy. Prescribing patterns were assessed for the first 3 treatment lines by year of initiation. RESULTS: Of the 66,846 patients receiving 1st line treatment, 63,289 (95.5%) were mHSPC and 3,557 (5.3%) were nmCRPC. NHT use steadily increased from 20% of treatments in 2018 to 30% in 2021 for mHSPC and 49% to 82% in nmCRPC. Compared to urologists, oncologists were more likely to prescribe NHT for mHSPC at each time point (Figure 1, 36%, n=511, vs 15%, n=104, p<0.001) but similar trends were not observed in treatment of nmCRPC (Figure 2). Starting in 2018, NHTs accounted for 40-47% and 43-96% of subsequent line treatments in HSPC and nmCRPC, respectively. CONCLUSIONS: Since FDA approval in 2018, NHT for HSPC and nmCRPC has steadily increased but still remains underutilized. Further study is needed to determine barriers to implementation of guideline concordant use of NHT for mHSPC and nmCRPC among both urologists and oncologists. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e457 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Daniel D. Joyce More articles by this author Vidit Sharma More articles by this author Andrew Zganjar More articles by this author Eugene D. Kwon More articles by this author R. Jeffrey Karnes More articles by this author Expand All Advertisement PDF DownloadLoading ...

Novel MDM2 Inhibitor XR-2 Exerts Potent Anti-Tumor Efficacy and Overcomes Enzalutamide Resistance in Prostate Cancer

Background: The inactivation of tumor-suppressor p53 plays an important role in second generation anti-androgens (SGAs) drug resistance and neuroendocrine differentiation in castration-resistant prostate cancer (CRPC). The reactivation of p53 by blocking the MDM2–p53 interaction represents an attractive therapeutic remedy in cancers with wild-type or functional p53. Whether MDM2-p53 inhibitor could overcome SGAs drug resistance in CRPC is still needed further research. Here, we investigated the anti-tumor efficacy and mechanisms of a novel MDM2-p53 inhibitor XR-2 in CRPC. Methods: To investigate the functions and mechanisms of XR-2 in prostate cancer, in vitro and in vivo biofunctional assays were performed. Western blot and qRT-PCR assay were performed to detect the protein and mRNA expression levels of indicated genes. CCK8, colony formation, flow cytometry and senescence assays were performed for cell function identifications. RNA-sequencing and bioinformatics analysis were mainly used to identify the influence of XR-2 on prostate cancer cells transcriptome. Subcutaneous 22Rv1 derived xenografts mice model was used to investigate the in vivo anti-tumor activity of XR-2. In addition, the broad-spectrum anti-tumor activities in vivo of XR-2 were evaluated by different xenografts mice models. Results: XR-2 could directly bind to MDM2, potently reactivate the p53 pathway and thus induce cell cycle arrest and apoptosis in wild-type p53 CRPC cell lines. XR-2 also suppresses the AR pathway as p53 regulates AR transcription inhibition and MDM2 participates in AR degradation. As a result, XR-2 efficiently inhibited CRPC cell viability, showed a synergistic effect with enzalutamide and overcame enzalutamide resistance both in vitro and in vivo. Moreover, results illustrated that XR-2 possesses broad-spectrum anti-tumor activities in vivo with favourable safety. Conclusion: MDM2-p53 inhibitor (XR-2) possesses potently prostate cancer progresses inhibition activity both in vitro and in vivo. XR-2 shows a synergistic effect with enzalutamide and overcomes enzalutamide resistance.

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.

A Synthetic Small Molecule Carbazole SH-I-125 Degrades Androgen Receptor and Overcomes Castration-Resistance and Enzalutamide-Resistance in Prostate Cancer Cells

Resistance to clinical anti-androgens is an ongoing problem in the treatment of castration-resistant prostate cancer (CRPC). Although second generation anti-androgens demonstrate initial clinical benefit, patients often develop resistance to these therapies, evidenced by rising serum PSA levels and disease progression. Several mechanisms including the expression of androgen receptor (AR) splice variants contribute to the reactivation of AR signaling in drug-resistant prostate cancer. Novel therapies that target AR signaling and suppress growth in castration-resistant and anti-androgen-resistant prostate cancer are essential for the effective management of advanced disease. We developed a synthetic small molecule analog of mahanine, SH-I-125, a compound with the ability to disrupt androgen receptor signaling and induce apoptosis in castration-resistant and drug-resistant prostate cancer cellular models. SH-I-125 disrupted AR signaling and induced apoptosis in CRPC cells and anti-androgen-resistant prostate cancer cells in a manner more effective than clinical anti-androgens, enzalutamide and ARN509. Furthermore, SH-I-125 decreased full-length AR and its splice variant AR-V7 levels in 22Rv1 prostate cancer cells by a proteasome-dependent mechanism. These findings indicate the therapeutic potential of SH-I-125 in prostate cancer patients that have progressed on currently approved therapies for CRPC.