Therapy For Advanced Prostate Cancer Research Articles

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.

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.

Disseminated superficial actinic porokeratosis in an elderly patient undergoing androgen deprivation therapy for advanced prostate cancer: exploring the potential association

Porokeratosis is a group of chronic dermatoses characterized by the presence of cornoid lamellae. Disseminated superficial actinic porokeratosis (DSAP) is a common subtype, presenting as multiple small annular scaly lesions primarily in sun-exposed areas. While previous studies have documented DSAP in prostate cancer patients, the association with androgen deprivation therapy (ADT) has not been reported. In this report, we describe an elderly patient with advanced prostate cancer, who developed DSAP subsequent to undergoing ADT. We present the clinical, dermoscopic, and histopathological evaluations, and discuss the potential role of ADT in the pathogenesis of DSAP.

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.

Prospective Assessment of Bone Metabolism Biomarkers and Survival in Metastatic Castration-resistant Prostate Cancer Patients Treated with Radium-223: The PRORADIUM Study

BackgroundRadium-223 is an active therapy option for bone metastatic castration-resistant prostate cancer (mCRPC). The lack of adequate biomarkers for patient selection and response assessment are major drawbacks for its use. ObjectiveTo assess the prognostic value of bone metabolism biomarkers (BMBs) in ra-223–treated mCRPC patients. Design, setting, and participantsA prospective cohort study of mCRPC patients treated with Ra-223 (PRORADIUM study: NCT02925702) was conducted. Outcome measurements and statistical analysisThe main objective of the study was to evaluate the association between high (≥median) baseline values in at least three bone formation (bone alkaline phosphatase [BAP] and C-terminal type-I collagen propeptide) and bone resorption (N-terminal telopeptide and pyridinoline) biomarkers, and survival. The independent prognostic value of each BMB was also assessed. The association with time to radiographic, clinical, and prostate-specific antigen (PSA) progression; time to skeletal-related events; and PSA response were secondary objectives. Multivariable (MV) Cox-regression models were evaluated. Results and limitationsA total of 169 patients were included. Of the patients, 70.4% received Ra-223 in second/third line; 144 (85.2%) were Eastern Cooperative Oncology Group 0–1, 126 (74.6%) were in pain, and 80 (47.5%) had more than ten bone metastases. Sixty-seven (39.6%) patients had elevation in at least three BMBs. The median overall survival was 12.1 mo (95% confidence interval [CI]: 10–14.7). No association was observed with other treatment-related secondary outcome parameters. Patients with high values in three or more BMBs had significantly worse survival (9.9 vs 15.2 mo; hazard ratio [HR]: 1.8 [95% CI: 1.3–2.5]; p < 0.001) in the univariate analysis, but not independent in the MV analysis (HR: 1.33; 95% CI: 0.89–2; p = 0.181). High baseline BAP was the only biomarker associated with survival in the MV model (HR: 1.89; 95% CI: 1.28–2.79; p = 0.001). Addition of BAP to the MV clinical model increased the area under the receiver operating characteristic curve 2-yr value from 0.667 to 0.755 (p = 0.003). ConclusionsBiomarkers of bone formation, especially BAP, have prognostic value in mCRPC patients treated with radium-223. Its predictive value remains to be assessed, ideally in prospective, adequately powered, randomised clinical trials. Patient summaryIn this study, we evaluate the role of bone metabolism biomarkers to help improve the use of radium-223 as therapy for advanced prostate cancer. We found that bone alkaline phosphatase may be a suitable tool.

Financial toxicity of oral therapies in advanced prostate cancer.

The treatment landscape of advanced prostate cancer (CaP) has evolved significantly over the past 20 years. As the number of oral anticancer treatment options continues to increase, so do the costs of these drugs. Furthermore, payment responsibility for these treatments is increasingly shifted from insurers to patients. In this narrative review, we sought to summarize existing assessments of financial toxicity (FT) associated with oral advanced CaP treatments, describe efforts targeted at limiting FT from these agents, and identify areas in need of further investigation. FT is understudied in advanced CaP. Oral treatment options are associated with significantly higher direct costs to patients compared to standard androgen deprivation therapy or chemotherapy. Financial assistance programs, Medicare low-income subsidies, and recent health policy changes help offset these costs for some patients. Physicians are reluctant to discuss treatment costs with patients and further work is needed to better understand best practices for inclusion of FT discussions in shared decision-making. Oral therapies for advanced CaP are associated with significantly higher patient out-of-pocket costs which may contribute to FT. Currently, little is known regarding the extent and severity of these costs on patients' lives. While recent policy changes have helped reduce these costs for some patients, more work is needed to better characterize FT in this population to inform interventions that improve access to care and lessen the harms associated with the cost of novel treatments.

Estimating the Impact of the Inflation Reduction Act on the Out-of-pocket Costs for Medicare Beneficiaries With Advanced Prostate Cancer.

Combination systemic therapy for advanced prostate cancer has reduced mortality, but high out-of-pocket costs impose financial barriers for patients. The Inflation Reduction Act's $2,000 out-of-pocket spending cap for Medicare's prescription drug benefit (Part D) can potentially lower out-of-pocket spending for beneficiaries starting in 2025. This study aims to compare out-of-pocket spending for commonly prescribed regimens for advanced prostate cancer before and after implementation of the Inflation Reduction Act. Medication regimens constructed to treat metastatic, hormone-sensitive prostate cancer consisted of baseline androgen deprivation therapy with traditional chemotherapy, androgen receptor inhibitors, and androgen biosynthesis inhibitors. Using 2023 Medicare Part B prices and the Medicare Part D plan finder, we estimated annual out-of-pocket costs under current law and under the Inflation Reduction Act's redesigned standard Part D benefit. Under current law, out-of-pocket costs for Part D drugs ranged from $464 to $11,336 per year. Under the Inflation Reduction Act, annual out-of-pocket costs for 2 regimens remained unchanged: androgen deprivation therapy with docetaxel and androgen deprivation therapy with abiraterone and prednisone. However, out-of-pocket costs for regimens using branded novel hormonal therapy were significantly lower under the 2025 law with potential savings estimated to be $9,336 (79.2%) for apalutamide, $9,036 (78.7%) for enzalutamide, and $8,480 (76.5%) for docetaxel and darolutamide. The $2,000 spending cap introduced by the Inflation Reduction Act may significantly decrease out-of-pocket costs and reduce financial toxicity associated with advanced prostate cancer treatment, impacting an estimated 25,000 Medicare beneficiaries.

Current Trends in Chemotherapy in the Treatment of Metastatic Prostate Cancer.

Prostate cancer is the second most common cancer among men. Despite advances in diagnosis and management, prostate cancer led to more than 300,000 deaths globally in 2020. Chemotherapy is a cornerstone of therapy for advanced prostate cancer and can prolong survival of patients with both castration-sensitive and castration-resistant disease. Herein, we present a comprehensive review of the data supporting implementation of chemotherapy in the modern treatment of advanced prostate cancer, with special attention to the use of chemotherapy for aggressive variant prostate cancer (e.g., neuroendocrine prostate cancer) and the combination of chemotherapy with androgen signaling inhibitors. As the field of prostate cancer research continues to rapidly evolve yielding novel agents and treatment modalities, chemotherapy continues to play an essential role in prolonging the survival of patients with advanced and metastatic prostate cancer.

Therapeutic efficacy and safety results of 177Lu-PSMA therapy in metastatic castration-resistant prostate cancer patients: first experience of a developing South Asian Country.

Metastatic castration resistant-prostate cancer (mCRPC) is deadly condition that remains incurable despite various therapies. Initial studies have shown promising results with Lutetium-177 prostate-specific membrane antigen ( 177 Lu-PSMA) therapy for advanced prostate cancer. However, most of the published efficacy and safety data is retrospective. The purpose of the study was to prospectively evaluate the therapeutic efficacy and safety results of 177 Lu-PSMA therapy in mCRPC patients after 2 cycles. Twenty-five patients of mCRPC, treated with standard care treatment were enrolled for 2 cycles of 177 Lu-PSMA therapy. Prostate-specific antigen (PSA), Eastern Cooperative Oncology Group (ECOG) performance status, Visual Analogue Score (VAS) and Analgesic Quantification Scale (AQS) for efficacy and hemoglobin, total leukocyte, platelets and serum creatinine for toxicity were recorded pre and post-therapy. Paired sample t-test was used for statistical analysis. Treated patients with mean PSA level of 157 ng/ml received mean dose of 6.84 GBq of 177 Lu-PSMA. For PSA, partial response (PR) was seen in 11/25 (44%), stable disease (SD) in 8/25 (32%) and progressive disease (PD) in 6/25 (24%) patients. Grade 1 and 2 hemoglobin toxicity was seen in 5/25 (20%) and 6/25 (24%) patients respectively. No patient developed grade 3 or 4 bone marrow toxicities. Grade 1 and 2 nephrotoxicity was seen in 1 patient each. Statistically significant difference was seen in ECOG, VAS and AQS scores ( P < 0.001). No significant nephrotoxicity was observed ( P = 0.558). Efficacy and safety of 177 Lu-PSMA therapy after 2 cycles have shown significant PSA response and pain palliation in heavily pretreated mCRPC patients.

An unbiased seed-based RNAi selection screen identifies small RNAs that inhibit androgen signaling and prostate cancer cell growth

Blocking androgen receptor signaling is the mainstay of therapy for advanced prostate cancer (PCa). However, acquired resistance to single agents targeting this pathway results in the development of lethal castration-resistant PCa. Combination therapy approaches represent a promising strategy for the treatment of advanced disease. Here, we explore a therapeutic strategy for PCa based on the ability of shRNAs/siRNAs to function essentially as miRNAs and, via seed sequence complementarity, induce RNA interference of numerous targets simultaneously. We developed a library that contained shRNAs with all possible seed sequence combinations to identify those ones that most potently reduce cell growth and viability when expressed in PCa cells. Validation of some of these RNAi sequences indicated that the toxic effect is associated with seed sequence complementarity to the 3' UTR of AR coregulatory and essential genes. In fact, expression of siRNAs containing the identified toxic seed sequences led to global inhibition of AR-mediated gene expression and reduced expression of cell-cycle genes. When tested in mice, the toxic shRNAs also inhibited castration-resistant PCa and exhibited therapeutic efficacy in pre-established tumors. Our findings highlight RNAi of androgen signaling networks as a promising therapeutic strategy for PCa.

Quantifying the changes in body mass index and performance status during androgen deprivation therapy for advanced prostate cancer in southeast Nigeria

BackgroundAndrogen deprivation therapy (ADT) for advanced prostate cancer (aPCa) causes changes in body mass index (BMI) and in the performance status depending on the extent of cancer remission. The aim of this study is to quantify these changes.MethodsA prospective cohort study in a public tertiary urology centre in Enugu, southeast Nigeria. With appropriate sample size determined, men with aPCa for ADT, by surgical or medical modality, were recruited into a test group (TG), taking note of the Gleason score. A cohort of similar men without malignant or debilitating diseases formed the control group (CG). The age, weight and the Eastern Cooperative Oncology Group (ECOG) score were determined before ADT and at 2 monthly intervals for the TG. Same parameters were assessed for the CG at 2 monthly intervals. Additionally, total prostate-specific antigen (tPSA) was done for the TG at 3 monthly intervals.ResultsIn all, 119 men in the TG and 68 men in the CG were recruited with no differences in age (F 2.777; p 0.10) and height (F 0.409; p 0.52) at recruitment. In the TG, BMI increased from 25.20 ± 3.92 to 26.26 ± 3.90 kg/m2 (p 0.001), median tPSA dropped from 36.9 ng/ml (IQR 20.4–65.7) to 3.7 ng/ml (IQR 1.1–8.7) and ECOG score improved (χ2 34.1; df9; p < 0.001) with reduction in the proportion of men with ECOG > 1 from 84.0 to 20.4%. A secondary finding is that gains in BMI and in ECOG score are earlier in the surgical modality than in the medical modality of ADT.ConclusionsIn the first 6 months of ADT, there are gains in BMI and ECOG scores. These gains are earlier with surgical modality of ADT.

Consensus on safety management of novel hormonal therapy for advanced prostate cancer

AbstractProstate cancer (PCa) is one of the most prevalent malignant tumors in men, accompanied by high incidence and mortality rates. Novel hormonal therapy (NHT) has emerged as the primary treatment for advanced PCa, providing noticeable clinical benefits. However, the diverse range of adverse events (AEs) associated with NHT may influence both treatment efficacy and patients' quality of life. In light of the latest international clinical research evidence and recommendations from domestic and foreign guidelines, this consensus aims to provide a comprehensive overview of the common AEs experienced during NHT for advanced PCa patients. Additionally, it seeks to develop a hierarchical approach to more efficiently manage AEs, presenting valuable insights for clinical medication and adverse reaction management.