Therapy For Advanced Prostate Cancer Research Articles

Talazoparib for the Treatment of Metastatic Castration-resistant Prostate Cancer

Breast and prostate cancer are among the most commonly diagnosed cancers worldwide. Recent advances in tumor sequencing and gene studies have led to a paradigm shift from treatment centered on the type of tumor to therapy more focused on specific immune phenotype markers and molecular alterations. In this review, we discuss the utility and function of talazoparib concerning prostate cancer treatment and summarize recent and planned clinical trials on talazoparib. We searched medical databases for articles relating to the use of talazoparib in prostate cancer from inception. Poly ADP ribose polymerase (PARP) is a family of 17 necessary DNA repair enzymes responsible for base excision repair, single-strand break repair, and double-strand break repair. PARP inhibitors are a class of oral targeted therapies that compete for the NAD+ binding site on PARP molecules. Talazoparib, a potent PARP inhibitor, has emerged as a significant therapeutic option in the treatment of metastatic castration-resistant prostate cancer (mCRPC), particularly for patients with specific genetic alterations. Its role as a PARP inhibitor makes it a targeted therapy, focusing on cancer cells with DNA repair deficiencies. Talazoparib’s role as a biomarker-directed therapy in advanced prostate cancer has been increasingly recognized. The TALAPRO-1 demonstrated durable antitumor activity in mCRPC patients. TALAPRO-2 is a notable clinical trial, specifically examining the effectiveness of Talazoparib when used in combination therapies. Current investigations demonstrate a significant improvement in survival outcomes for the patients of mCRPC, making Talazoparib a promising intervention.

A PSMA-targeted Tri-specific Killer Engager enhances NK cell cytotoxicity against prostate cancer.

Natural killer (NK) cell tumor infiltration is associated with good prognosis in patients with metastatic castration-resistant prostate cancer (mCRPC). NK cells recognize and kill targets by a process called natural cytotoxicity. We hypothesized that promoting an antigen-specific synapse with co-activation may enhance NK cell function in mCRPC. We describe a Tri-specific Killer Engager (TriKE) construct that engages with the activating receptor CD16 on NK cells, prostate-specific membrane antigen (PSMA) on mCRPC cells, and has an interleukin (IL)-15 moiety that is essential for NK cell survival, proliferation, and priming. We show that the PSMA TriKE specifically binds to PSMA-expressing cells and significantly enhances expansion, degranulation and cytokine production of NK cells derived from healthy donors or prostate cancer patients. Bystander killing of PSMA-negative was also achieved with PSMA TriKE treatment when co-cultured with PSMA-positive cells, suggesting potential PSMA TriKE benefit in controlling tumor antigen escape. When tested under physiologic conditions recapitulating the mCRPC tumor microenvironment (TME), NK cells treated with PSMA TriKE and prolonged exposure to hypoxia or MDSCs maintained their potent function while IL-15 treated NK cells showed greatly impaired cytotoxicity. Finally, in vivo testing of PSMA TriKE showed improved tumor control and survival of mice as compared to IL-15 and untreated control groups. In conclusion, PSMA TriKE demonstrates potential as a new therapy for advanced prostate cancer by providing additional signals to NK cells to maximize their anti-tumor potential in prostate cancer, especially in the setting of a hostile TME.

Vaccination Against Androgen Receptor Splice Variants to Immunologically Target Prostate Cancer.

Background/Objectives: Androgen receptor (AR) expression and signaling are critical for the progression of prostate cancer and have been the therapeutic focus of prostate cancer for over 50 years. While a variety of agents have been developed to target this axis, many of these fail due to the emergent expression of AR RNA splice variants, such as AR-V7, that can signal independently of ligand binding. Other therapies, such as vaccination against prostate-specific antigens, have achieved FDA approvals but have fallen short of being incorporated as standard-of-care therapies for advanced prostate cancer. This may be due to the elevated level of immunosuppression observed in prostate cancer, which remains largely refractory to immune checkpoint blockade. Methods: We developed a vaccine targeting AR-V7, a common isoform associated with treatment resistance, and demonstrated its ability to elicit AR-V7-specific immunity and enable anti-tumor responses against AR-V7+ cancers in subcutaneous tumor models. Results: Our studies also revealed that AR-V7 expression conferred an immune suppressive phenotype that was significant in a non-AR-dependent prostate cancer model. Notably, in this model, we found that vaccination in combination with enzalutamide, an AR antagonist, suppressed these aggressive immune suppressive cancers and resulted in enhanced survival in comparison to control vaccinated and enzalutamide-treated mice. While anti-PD-1 immune checkpoint inhibition (ICI) alone slowed tumor growth, the majority of vaccinated mice that received anti-PD-1 therapy showed complete tumor elimination. Conclusions: Collectively, these results validate the importance of AR signaling in prostate cancer immune suppression and suggest the potential of AR-V7-specific vaccines as therapeutic strategies against prostate cancer, offering significant protective and therapeutic anti-tumor responses, even in the presence of androgen signaling inhibitors.

Plain language review: the safety of relugolix combination therapy for advanced prostate cancer.

Advanced prostate cancer is a cancer that began in the prostate (a part of the male body) and has spread to other parts of the body. This is a review of two clinical research studies of patients with advanced prostate cancer who were treated with relugolix combination therapy. Relugolix is a medicine taken by mouth that lowers a male sex hormone, called testosterone. Relugolix is sometimes combined with other medicines such as novel hormonal therapies (NHTs) or chemotherapy to treat advanced prostate cancer. In one study, patients were treated with relugolix combined with an NHT (abiraterone or apalutamide). In a second study, patients were treated with relugolix combined with an NHT (enzalutamide) or chemotherapy (docetaxel). Researchers wanted to understand what possible side effects may happen due to taking these medicines together as prescribed. They also wanted to see if relugolix combination therapy worked to lower testosterone in the same way as relugolix taken alone. Researchers found that most of the side effects of relugolix combined with an NHT or chemotherapy were mild or moderate. Side effects of relugolix combination therapy were similar to the side effects of the medicines when taken alone. However, patients who received relugolix with enzalutamide or docetaxel were more likely to have a serious side effect compared with patients who received relugolix taken alone. Testosterone stayed below 50 nanograms per deciliter (known as castration levels) for patients who received relugolix with NHT or chemotherapy. Patients who receive relugolix combination therapy generally experience mild or moderate side effects, rather than serious side effects. No new safety issues were found during these studies. Patients maintained low testosterone levels. Patients and their doctors should discuss the benefits and possible harms of relugolix combination therapy to treat advanced prostate cancer.

Germline genetic testing for prostate cancer: Ordering trends in the era of expanded hereditary cancer screening recommendations

PurposeThe availability of targeted therapies for advanced prostate cancer led to the expansion of national guidelines recommending germline genetic testing. The aim of this study was to describe recent trends in germline test ordering patterns for patients with prostate cancer. Materials and MethodsA retrospective cohort analysis of patients with prostate cancer who underwent germline testing through a single commercial laboratory (Invitae Corporation) between 2015–2020 was performed. Ordering trends between provider medical specialties were compared. Our primary hypothesis was that the proportion of tests ordered by urologists would increase over time. ResultsIn total, 17,256 prostate cancer patients underwent germline genetic testing; 14,400 patients had an ordering provider with an associated medical specialty and were included in the final comparison cohort. Total prostate cancer patients undergoing germline testing increased quarterly from 21 in Q2 of 2015 to 1,509 in Q3 of 2020. The proportion of tests ordered by urologists increased from 0% in Q2 2015 to 8.3% in Q3 2020 (P < 0.001). Compared to medical genetics, medical oncology, and other specialties, urology ordered more tests for patients under 70 years old (66% vs 51%–55%, P <0.004) and for patients who reported negative family history (25% vs 12%–20%, P = 0.012). ConclusionsAs awareness and indications for germline testing continue to expand, aggregate ordering volume is increasing, and urologists are becoming more involved in facilitating testing. This highlights the continued importance of educating urologists on the indications for and implications of germline genetic testing, as well as providing tools to support implementation.

LX1 Dual Targets AR Variants and AKR1C3 in Advanced Prostate Cancer Therapy.

The development of resistance to current standard-of-care treatments, such as androgen receptor (AR) targeting therapies, remains a major challenge in the management of advanced prostate cancer. There is an urgent need for new therapeutic strategies targeting key resistant drivers, such as AR variants like AR-V7, and steroidogenic enzymes, such as aldo-keto reductase 1C3 (AKR1C3), to overcome drug resistance and improve outcomes for patients with advanced prostate cancer. Here, we have designed, synthesized, and characterized a novel class of LX compounds targeting both the AR/AR variants and AKR1C3 pathways. Molecular docking and in vitro studies demonstrated that LX compounds bind to the AKR1C3 active sites and inhibit AKR1C3 enzymatic activity. LX compounds were also shown to reduce AR/AR-V7 expression and to inhibit their target gene signaling. LX1 inhibited the conversion of androstenedione into testosterone in tumor-based ex vivo enzyme assays. In addition, LX1 inhibited the growth of cells resistant to antiandrogens including enzalutamide (Enza), abiraterone, apalutamide, and darolutamide in vitro. A synergistic effect was observed when LX1 was combined with antiandrogens and taxanes, indicating the potential for this combination in treating resistant prostate cancer. Treatment with LX1 significantly decreased tumor volume, serum PSA levels, as well as reduced intratumoral testosterone levels, without affecting mouse body weight. Furthermore, LX1 was found to overcome resistance to Enza treatment, and its combination with Enza further suppressed tumor growth in both the CWR22Rv1 xenograft and LuCaP35CR patient-derived xenograft models. Collectively, the dual effect of LX1 in reducing AR signaling and intratumoral testosterone, along with its synergy with standard therapies in resistant models, underscores its potential as a valuable treatment option for advanced prostate cancer. Significance: LX1 simultaneously targets androgen receptor variants and the steroidogenic enzyme AKR1C3, offering a promising approach to combat drug resistance and enhancing therapeutic efficacy in conjunction with standard treatments for advanced prostate cancer.

Prescription Medications and Overall Survival in Metastatic Hormone Sensitive Prostate Cancer.

With new therapies for metastatic prostate cancer, patients are living longer, increasing the need for better understanding of the impact of comorbid disease. Prescription medications may risk-stratify patients independent of established methods, such as the Charlson Comorbidity Index (CCI) and guide treatment selection. In a nationwide retrospective study of US Veterans, we used multivariable logistic regression and Cox proportional hazard modeling to evaluate the association between number and class of prescription medications and overall survival (OS) with age, race, body-mass index, prostate specific antigen (PSA), and Charlson comorbidities as covariates in veterans treated for de novo metastatic hormone sensitive prostate cancer (mHSPC) between 2010-2021. Among 8,434 Veterans, a median of nine medications and five medication classes were filled in the year prior to initial treatment with abiraterone or enzalutamide for mHSPC. Veterans on 1-4 medications had an average survival of 38 months compared to 5-9 medicines (33 months), 10-14 medicines (27 months), and 15+ medicines (22 months) (p<0.001). After adjusting for age, race, body mass index (BMI), PSA, CCI, and year of diagnosis, both the number of medications and medication classes were associated with increased mortality. The adjusted hazard ratio (aHR) [95% confidence interval (CI)] was 1.03 (1.02-1.03) for the number of medications and 1.05 (1.04-1.07) for medication classes. Medications within ATC B (blood/blood forming organs), ATC C (cardiovascular), and ATC N (nervous) were associated with worse OS, with aHRs of 1.14 (1.07, 1.21), 1.14 (1.06, 1.22), and 1.12 (1.06, 1.19), respectively. The number and class of medications were independently associated with overall survival in patients undergoing treatment for mHSPC. With new therapies for advanced prostate cancer, patients are living longer, highlighting the need for a better understanding of the impact of comorbid diseases. Simple methods to assess disease burden and prognosticate survival have the potential to guide treatment decisions.

The 340B Program and High-Risk Prescribing of Oral Targeted Therapies for Advanced Prostate Cancer.

The use of expensive oral targeted agents for advanced prostate cancer can be influenced by those who stand to gain from their use. The 340B drug pricing program allows eligible hospitals to purchase medications at steep discounts, generating millions of dollars in savings. The extent to which hospitals engage in higher-risk prescribing due to program incentives is unclear. Medicare claims were used to perform a retrospective study of men with advanced prostate cancer. The primary outcome was targeted therapy use in men with high noncancer mortality risk. Secondary outcomes included androgen biosynthesis inhibitor use in men with cardiovascular history, androgen receptor inhibitor use in men with neurocognitive history, and therapy within 14 days of death. Proportional hazards models were used to assess time-to-event outcomes, while logistic regression was used for binary outcomes. In men with high noncancer mortality risk, targeted therapy use did not differ at 340B participating compared to nonparticipating hospitals (hazard ratio [HR] 1.1, 95% CI 0.67-1.5). There was no difference in androgen biosynthesis inhibitor use in men with a prior cardiac event (HR 0.96, 95% CI 0.70-1.3) or androgen receptor inhibitor use in men with a prior neurocognitive event (HR 1.5, 95% CI 0.65-3.4) in those treated at 340B participating compared to nonparticipating hospitals. Therapy use in the last 14 days of life did not vary by 340B participation (odds ratio 1.3, 95% CI 0.86-1.9). In men with advanced prostate cancer, high-risk prescribing and futility measures did not vary by participation in the 340B drug pricing program.

Androgen deprivation therapy in advanced prostate cancer: insights from a real-world patient survey on health-related quality of life and information and communication sources.

Androgen deprivation therapy (ADT) is a cornerstone treatment for advanced and metastatic prostate cancer. Real-world and patient-reported insights into ADT's impact on health-related quality of life (HRQoL) and communication experiences in healthcare settings remain underexplored. This patient organisation-initiated online survey aimed to assess these aspects. Between December 2022 and August 2023, the patient organisation Think Blue Vlaanderen and the AZ Sint-Jan Hospital (Bruges, Belgium) invited ADT-treated patients to participate in a prospective, online, cross-sectional, patient-reported outcome survey. Demographic, clinical, HRQoL (FACT and EPIC-26), communication sources and information modality data were collected. Descriptive statistics and comparative analyses were applied. A total of 276/312 (88.5%) participating patients were on ADT at time of survey administration and completion, with the majority receiving a 3-monthly regimen. Sexual HRQoL was low and narrowly distributed (median (IQR): 16.7 (16.7-16.7)), with 84% of patients having erectile dysfunction (ED). Patients finding their ED problematic were more likely to seek pharmaceutical treatment. Hormonal HRQoL was widely distributed (median (IQR): 65 (45-85)), which improved with prolonged ADT duration. Physically active patients reported less lack of energy, but increased hot flashes. Within consistent FACT-G summary scores (median (IQR): 64.50 (54.75-77.00)), improved emotional wellbeing with prolonged ADT was noted. Multidisciplinary communication and multimodal information provision improved patient satisfaction. Patient organisation-initiated surveys offer real-world and patient-reported insights. Patient-tailored HRQoL assessments and longitudinal follow-up, physical activity, and multidisciplinary and multimodal communication approaches are warranted to improve patient-centred care in patients receiving ADT.

Development of a Novel Patient-Reported Outcome Measure to Assess Symptoms and Impacts of Androgen Deprivation Therapy for Advanced Prostate Cancer.

This qualitative research study was conducted to develop a novel, comprehensive, patient-reported outcome measure (PRO), the "Symptoms and Impacts of Androgen Deprivation Therapy (ADT) for Prostate Cancer" (SIADT-PC), assessing hormonal therapy-related symptoms and their impacts on men with advanced prostate cancer. Concept elicitation (CE) interviews were conducted among adult men with prostate cancer to evaluate their experiences with ADT. Based on key symptom and impact concepts mentioned, an initial PRO measure was developed. The draft measure was further assessed in cognitive debriefing (CD) interviews with men with prostate cancer, in which participants reviewed items, response options, and recall periods. Initial item-based psychometric analyses were conducted using interview data. The draft questionnaire was revised on the basis of participant feedback, quantitative psychometric results, and consultation with clinical experts. A total of 21 participants were interviewed (CE concept elicitation, n = 12; CD cognitive debriefing, n = 17; n = 8 completed both). Mean participant age (SD) was 59.7 (8.7) years and 76.2% were white. The de novo SIADT-PC measure consists of 27 items: 11 symptoms (e.g., fatigue, hot flashes, and erectile dysfunction), 2 long-term symptoms (e.g., weight gain), 10 impacts (e.g., impacts on physical activities and relationships), and 4 related to mode of administration (i.e., injection-site reactions). Items were assessed with a 5-point verbal rating scale, with answer choices that capture frequency or severity. Once fully validated, this de novo measure may be used in clinical studies and clinical practice to assess hormone therapy-related symptoms and impacts, enabling physicians to identify timely and appropriate interventions.

Differences in real-world outcomes by risk classification for localized prostate cancer patients after radiation therapy.

Limited real-world evidence exists on the long-term clinical outcomes of patients with localized prostate cancer (LPC) who received external beam radiation therapy (EBRT) as the initial treatment. This study evaluated clinical outcomes of US patients with high-risk LPC (HR-LPC) and low/intermediate-risk LPC (LIR-LPC) who received EBRT. This retrospective study using Surveillance, Epidemiology, and End Results-Medicare linked data from 2012 to 2019 included patients ≥ 65 years old who received EBRT as initial therapy. Baseline patient characteristics were summarized, metastasis-free survival (MFS), overall survival, and time to initiation of advanced prostate cancer treatment were compared using Kaplan-Meier (KM) and adjusted Cox proportional hazard (PH) models. 5-year survival probabilities stratified by race/ethnicity (non-Hispanic [NH] White, NH Black, NH Asian, and Hispanic) were assessed. Of 11,313 eligible patients, 41% (n = 4600) had HR-LPC and 59% (n = 6713) had LIR-LPC. Patient characteristics for both groups were comparable, with mean age at EBRT initiation > 70 years, 86% white, and mean follow-up time >40 months. More patients in the HR-LPC than LIR-LPC groups (78% vs 34%) had concurrent androgen deprivation therapy use and for a longer duration (median 10.4 months vs. 7.4 months). A higher proportion of HR-LPC patients developed metastasis, died, or received advanced prostate cancer treatment. Adjusted Cox PH survival analyses showed significantly (p < 0.0001) higher risk of mortality (hazard ratios[HR], 1.57 [1.38, 2.34]), metastasis or death (HR, 1.97 [1.78, 2.17]), and advanced prostate cancer therapy use (HR, 2.57 [2.11, 3.14]) for HR-LPC than LIR-LPC patients. Within 5 years after the initial EBRT treatment, 18%-26% of patients with HR-LPC are expected to have died or developed metastasis. The 5-year MFS rate in the HR-LPC group was lower than the LIR-LPC group across all racial/ethnic subgroups. NH Black patients with HR-LPC had the highest all-cause mortality rate and lowest rate of receiving advanced prostate cancer treatment, compared to other racial/ethnic subgroups. This real-world study of clinical outcomes in patients with LPC treated with EBRT suggests substantial disease burden in patients with HR-LPC and highlights the need for additional treatment strategies to improve clinical outcomes in patients with HR-LPC.

Abstract 1240: Enhancing NK cell function in the ‘cold’ tumor microenvironment of prostate cancer with a novel tri-specific killer engager

Abstract Introduction: Natural killer (NK) cells are associated with good prognosis in patients with metastatic castration-resistant prostate cancer (mCRPC). However, NK cell function is hindered in the immunosuppressive and hypoxic tumor microenvironment (TME) of mCRPC. To improve NK cell-mediated responses against mCRPC, we designed a novel Tri-specific Killer Engager (TriKE®) that engages with NK cell activating receptor CD16, binds to prostate-specific membrane antigen (PSMA) that is highly and specifically expressed on mCRPC, and has an interleukin (IL)-15 moiety that is essential for NK cell survival, proliferation, and priming. Methods: PSMA TriKE was produced using the mammalian expression system and tested using healthy donor and prostate cancer patient-derived NK cells. Flow cytometry-based functional and dye dilution proliferation assays were used to compare activation and proliferation of NK cells treated with PSMA TriKE or IL-15. NK cell cytolytic capacity against C4-2 cells, a PSMA-expressing prostate cancer line, was measured using IncuCyte live cell imaging. In various assays, hypoxic (1% oxygen) culture condition and cytokine-induced myeloid-derived suppressor cells (MDSC) were incorporated to better examine PSMA TriKE function in the physiological setting of mCRPC. In vivo testing of the PSMA TriKE was performed using C4-2 xenograft model and expanded NK cells in NSG mice. Results: PSMA TriKE significantly enhanced expansion of peripheral blood NK cells derived from healthy donors up to 8-fold. Additionally, PSMA TriKE induced significantly higher NK cell degranulation and intracellular IFNγ and TNFα buildup, when compared to IL-15 treatment, after incubation with C4-2 cells. Responses of NK cells derived from prostate cancer patients were equivalent to healthy controls. Although NK cell activation was not observed against PSMA knockout (KO) C4-2, indicating specificity of PSMA TriKE treatment, bystander killing of PSMA-KO C4-2 was achieved with PSMA TriKE treatment when wildtype C4-2 cells were cocultured. This suggests potential PSMA TriKE benefit in controlling tumor antigen escape, through natural cytotoxicity once primed. In settings that mimic the TME of mCRPC, NK cells treated with PSMA TriKE in prolonged exposure to hypoxia showed retention of cytotoxicity against C4-2 while IL-15 treated NK cells showed greatly impaired cytotoxicity. Similarly, MDSC suppressed NK cell cytotoxicity in the presence of IL-15, but PSMA TriKE treatment abrogated MDSC-induced suppression. Finally, PSMA TriKE enhanced tumor control and improved survival of mice as compared to IL-15 and no treatment groups in vivo. Conclusion: PSMA TriKE demonstrates potential in overcoming suppression of NK cells in the TME of mCRPC and is a promising candidate for advanced prostate cancer therapy. Citation Format: Shee Kwan Phung, Yvette Soignier, Nicholas Zorko, Rhett L. Waller, Josh Walker, Trygve Nelson, Carly Selleck, Laura Bendzick, Philippa Kennedy, Jeffrey S. Miller, Martin Felices. Enhancing NK cell function in the ‘cold’ tumor microenvironment of prostate cancer with a novel tri-specific killer engager [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 1240.

Updates on Overcoming Bicalutamide Resistance: A Glimpse into Resistance to a Novel Antiandrogen.

The standard androgen deprivation therapy for advanced prostate cancer includes the use of bicalutamide, which is a well-known antagonist of androgen receptors. Despite numerous benefits of the drugs in prostate cancer treatment, there is always a risk of developing a resistant phenotype, which paves the way for a more aggressive and low-survival type of prostate cancer. Over the years, many studies have investigated the candidate mechanisms of such resistance and have managed to find possible therapeutic solutions. In this Review, we shed light on the heterogeneous dynamics of progression to resistance against bicalutamide treatment, referring to the most recent studies and the approaches that have been so far discussed. This Review tries to offer a deep and comprehensive understanding about how the resistant cells become sensitive to the drug and what corresponding pathways lead to an appropriate solution for the antiandrogen resistance challenge.

ST3 beta-galactoside alpha-2,3-sialyltransferase 1 (ST3Gal1) synthesis of Siglec ligands mediates anti-tumour immunity in prostate cancer

Immune checkpoint blockade has yet to produce robust anti-cancer responses for prostate cancer. Sialyltransferases have been shown across several solid tumours, including breast, melanoma, colorectal and prostate to promote immune suppression by synthesising sialoglycans, which act as ligands for Siglec receptors. We report that ST3 beta-galactoside alpha-2,3-sialyltransferase 1 (ST3Gal1) levels negatively correlate with androgen signalling in prostate tumours. We demonstrate that ST3Gal1 plays an important role in modulating tumour immune evasion through the synthesises of sialoglycans with the capacity to engage the Siglec-7 and Siglec-9 immunoreceptors preventing immune clearance of cancer cells. Here, we provide evidence of the expression of Siglec-7/9 ligands and their respective immunoreceptors in prostate tumours. These interactions can be modulated by enzalutamide and may maintain immune suppression in enzalutamide treated tumours. We conclude that the activity of ST3Gal1 is critical to prostate cancer anti-tumour immunity and provide rationale for the use of glyco-immune checkpoint targeting therapies in advanced prostate cancer.

The effect of human leukocyte antigen genotype on survival in advanced prostate cancer treated with primary androgen deprivation therapy: the KYUCOG-1401-A study.

Immune editing, in which human leukocyte antigens (HLA) have critical roles, has been suggested to shape the landscape of human cancer. This study prospectively investigated whether HLA gene zygosity is associated with the prognosis of primary androgen deprivation therapy in advanced prostate cancer. KYUCOG-1401-A was conducted in conjunction with a prospective clinical trial (KYUCOG-1401). Among the patients enrolled in KYUCOG-1401 and treated with primary androgen deprivation therapy, only Japanese patients were included. HLA genotypes of HLA-A, B, C, DRB1, DQB1, and DPB1 were determined. The effect of divergence of HLA genotypes on time to progression, prostate cancer-specific survival, and overall survival was evaluated. Among 127 patients, homozygosity for HLA-DRB1 (HR, 95% CI; 4.05, 1.54-10.7, P = 0.0047) and HLA-DQB1 (HR, 95% CI; 3.75, 1.47-9.58, P = 0.0058) was associated with an increased risk of prostate cancer-specific mortality. Patients with higher HLA evolutionary divergence scores at HLA-DQB1 (HR, 95% CI; 0.90, 0.82-0.97, P = 0.0093) had lower risks of prostate cancer-specific mortality. Androgen-responsive gene sets were upregulated in CD4low and CD8low tumors in the prostate cancer cohort, but not in the bladder and kidney cancer cohorts. This study suggested that the diversity of HLA-II loci including HLA-DRB1 and HLA-DQB1 plays an important role in advanced prostate cancer survival, contributing to improved risk stratification in advanced prostate cancer. Moreover, it was shown that CD4+ T cells play an important role in androgen deprivation therapy, suggesting that immunotherapy targeting CD4+ T cells is promising for prostate cancer.

Androgen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through HGF and Wnt activation

Androgen deprivation therapy (ADT) targeting androgen/androgen receptor (AR)- signaling pathways is the main therapy for advanced prostate cancer (PCa). However, ADT eventually fails in most patients who consequently develop castration-resistant prostate cancer (CRPC). While more potent AR antagonists and blockers for androgen synthesis were developed to improve clinical outcomes, they also show to induce more diverse CRPC phenotypes. Specifically, the AR- and neuroendocrine-null PCa, DNPC, occurs in abiraterone and enzalutamide-treated patients. Here, we uncover that current ADT induces aberrant HGF/MET signaling activation that further elevates Wnt/β-catenin signaling in human DNPC samples. Co-activation of HGF/MET and Wnt/β-catenin axes in mouse prostates induces DNPC-like lesions. Single-cell RNA sequencing analyses identify increased expression and activity of XPO1 and ribosomal proteins in mouse DNPC-like cells. Elevated expression of XPO1 and ribosomal proteins is also identified in clinical DNPC specimens. Inhibition of XPO1 and ribosomal pathways represses DNPC growth in both in vivo and ex vivo conditions, evidencing future therapeutic targets.

Novel dual inhibitors of AR/AR variants and AKR1C3: Preclinical activities for advanced prostate cancer therapy.

Novel dual inhibitors of AR/AR variants and AKR1C3: Preclinical activities for advanced prostate cancer therapy.

Management of Advanced Prostate Cancer With Relugolix: Illustrative Case Scenarios From an Advanced Practice Provider Perspective.

Prostate cancer is the second most common cause of cancer-related mortality among men in the United States, with an estimated 34,700 deaths annually. Androgen deprivation therapy (ADT) is the cornerstone of advanced prostate cancer therapy, and injectable luteinizing hormone-releasing hormone (LHRH) agonists have served as the most commonly used ADT for over 30 years. Relugolix, a first-in-class, once-daily, oral gonadotropin-releasing hormone (GnRH) antagonist, was developed to address some of the limitations of available ADT therapies. Herein, we present two hypothetical case reports via an advanced practice provider (APP) perspective that reflect prototypical examples of patients with advanced localized disease not suitable for surgery or newly diagnosed hormone-sensitive metastatic disease treated with relugolix. The cases presented are meant to be instructional and within the scope of the current approved prescribing information for all medications mentioned. Best practices from an APP perspective are shared.

6-month Formulations of Androgen Deprivation Therapy for Advanced Prostate Cancer: Effectiveness and Rationale for Extended Dosing

Background: Luteinizing hormone-releasing hormone (LHRH) agonists and GnRH antagonists are the most widely used androgen deprivation therapy to achieve castration levels of serum testosterone (T). Adherence to dosing schedules is important to avoid treatment failure. A recent analysis found a high non-adherence rate of 84% for LHRH agonist injections based on dosing schedules used in pivotal trials. Method: Narrative review of LHRH therapy and evaluation of which offers optimal efficacy, safety, and practicality. Results: 6-month LHRH agonist formulations require fewer appointments for injections than shorter-acting formulations. Therefore, the frequency of late/missed doses and overall non-adherence may be reduced compared to options requiring frequent dosing (e.g., oral therapies and shorter-acting injections). This flexibility may be preferable for patients who live in multiple locations throughout the year, live long distances from clinics, and/or lack access to reliable transportation. 6-month formulations may also have cost benefits compared to shorter-acting doses. Despite similar levels of T suppression during the labeled dosing period, individual 6-month LHRH agonist formulations appear to have unique profiles, e.g., 6-month subcutaneous leuprolide acetate (LA) results in lower T escape rates compared to 6-month intramuscular LA, if dosing is late. Conclusion: The efficacy and practicality offered by 6-month LHRH formulations suggest these could reduce opportunities for late injections by requiring fewer office visits and provide greater confidence that efficacy will be maintained should there be extenuating circumstances leading to delays in therapy administration, as experienced during the recent pandemic.

Abstract 18762: Pacemaker Pocket Erosion - An Undesired Complication of Leuprolide Therapy

Introduction: Pacemaker pocket erosion is an uncommon delayed complication of the cardiac implantable electronic device (CIED) implantation that most frequently occurs in frail and elderly patients. We present a case of such a patient who developed pacemaker pocket erosion after being initiated on hormonal therapy for advanced prostate cancer. Case presentation: The patient is a ninety-three-year-old male with a history of persistent atrial fibrillation and dual chamber pacemaker in situ with last generator change two years prior presented with a two-week history of pacemaker wound dehiscence and exposed pacemaker. Six months earlier, the patient was diagnosed with advanced prostate cancer, was initiated on gonadotropin-releasing hormone agonist, leuprolide, and subsequently developed unintentional weight loss of 30 pounds. For two months prior to the current presentation, the patient noticed subjective discomfort at the site of the pacemaker pocket which he did not report to his cardiologist and eventually developed an erosive wound overlying the pacemaker pocket exposing the device (Image 1). He was admitted to the hospital and found to be hemodynamically stable, without leukocytosis and, negative blood cultures. Transthoracic and transesophageal echocardiograms showed no evidence of vegetation. He was empirically treated with daptomycin and was referred for pacing system extraction. He underwent pacing system replacement with leads and device extraction followed by leadless Micra VR (Medtronic, Minneapolis, MN) pacemaker implantation. Following a 4-week antibiotic course post pacemaker system extraction, the pacemaker pocket wound was fully healed. Conclusions: Aging and weight loss are known major risk factors for device-pocket erosion and externalization of the CIED. It highlights the importance of improving awareness of this entity and that initiation of hormonal therapy can be a contributing factor to such complications.