Therapy For Metastatic Prostate Cancer Research Articles

A nomogram model for determining optimal patients for local therapy in metastatic prostate cancer: a SEER database-based study

BackgroundNumerous studies have shown that local therapy can improve long-term survival in patients with metastatic prostate cancer. However, it is unclear which patients are the potential beneficiaries.MethodsWe obtained information on prostate cancer patients from the Surveillance, Epidemiology, and End Results database and divided eligible patients into the local treatment group and non-local treatment group. Propensity score matching (PSM) was used to reduce the influence of confounding factors. In the matched local treatment (LT) group, if the median overall survival time (OS) was longer than the Nonlocal treatment (NLT) group, it was defined as a benefit group, otherwise, it was a non-benefit group. Then, univariate and multivariate logistic regression were used to screen out predictors associated with benefits, and a nomogram model was constructed based on these factors. The accuracy and clinical value of the models were assessed through calibration plots and decision curve analysis.ResultsThe study enrolled 7255 eligible patients, and after PSM, each component included 1923 patients. After matching, the median OS was still higher in the LT group than in the NLT group [42 (95% confidence interval: 39–45) months vs 40 (95% confidence interval: 38–42) months, p = 0.03]. The independent predictors associated with benefit were age, PSA, Gleason score, T stage, N stage, and M stage. The nomogram model has high accuracy and clinical application value in both the training set (C-index = 0.725) and the validation set (C-index = 0.664).ConclusionsThe nomogram model we constructed can help clinicians identify patients with potential benefits from LT and formulate a reasonable treatment plan.

Patient outcomes following a response biomarker-guided approach to treatment using 177Lu-PSMA-I&T in men with metastatic castrate-resistant prostate cancer (Re-SPECT).

177LuPSMA is an effective treatment in metastatic castrate-resistant prostate cancer with trials adopting a standardised dose interval. Adjusting treatment intervals utilising early response biomarkers may improve patient outcomes. This study evaluated progression-free survival (PFS) and overall survival (OS) based on treatment interval adjustment utilising 177LuPSMA 24-h SPECT/CT (177Lu-SPECT) and early prostate-specific antigen (PSA) response. Retrospective analysis of a clinical 177Lu-PSMA-I&T treatment programme. In all, 125 men were treated with 6-weekly 177LuPSMA-I&T [median 3 cycles, interquartile range (IQR): 2-4], median dose 8.0 GBq [95% confidence interval (CI): 7.5-8.0]. Imaging screening involved 68GaPSMA-11 PET/diagnostic CT. 177Lu-SPECT/diagnostic CT was acquired following each therapy, and clinical assessments 3-weekly. Following dose 2 (week 6), a composite PSA and 177Lu-SPECT/CT imaging response [partial response (PR), stable disease (SD), and progressive disease (PD)] determined ongoing management. Response group (RG) 1 (marked reduction in PSA/imaging PR) break in treatment until subsequent PSA rise, then re-treatment. RG 2 (stable or reduced PSA and/or imaging SD) 6-weekly treatments until six doses, or no longer clinically benefitting. RG 3 (rise in PSA and/or imaging PD) recommended for an alternative treatment. Overall PSA50% response rate (PSARR) was 60% (75/125), median PSA-PFS 6.1 months (95%CI: 5.5-6.7), and median OS 16.8 months (95%CI: 13.5-20.1). 35% (41/116) were classified as RG 1, 34% (39/116) RG 2, and 31% (36/116) RG 3. PSARRs by RG were 95% (38/41), 74% (29/39), and 8% (3/36); median PSA-PFS rates were 12.1 months (95%CI: 9.3-17.4), 6.1 months (95%CI: 5.8-9.0), and 2.6 months (95%CI: 1.6-3.1); and OS rates were 19.2 months (95%CI: 16.8-20.7), 13.2 months (95%CI: 12.0-18.8), and 11.2 months (95%CI: 8.7-15.6) for RG 1, 2, and 3, respectively. The median months of 'treatment holiday' for RG 1 was 6.1 months (IQR: 3.4-8.7). Nine men had received prior 177LuPSMA-617 and were retreated with 177LuPSMA-I&T, with a PSARR of 56% on re-treatment. Personalising dosing regimens using early response biomarkers with 177LuPSMA has the potential to achieve similar treatment responses to continuous dosing while allowing treatment breaks or intensification. Further evaluation of early response biomarker-guided treatment regimens in prospective trials is warranted. Lutetium-PSMA therapy is a new therapy for metastatic prostate cancer that is well tolerated and effective. However, not all men respond equally, with some responding very well and others progressing early. Personalising treatments require tools that can accurately measure treatment responses, preferably early in the treatment course, so adjustments to treatment can be made. Lutetium-PSMA can measure tumour sites after each therapy by taking whole body 3D images at 24 h using a small radiation wave from the treatment itself. This is called a SPECT scan. Previous work has shown that both prostate-specific antigen (PSA) response and changes in tumour volume on a SPECT scan can predict how patients will respond to treatment as early as dose 2. This study demonstrates that stratifying how men are treated based on the results of the 6-week SPECT scan and PSA response potentially allows a third of men to have break in treatment and that these men have both longer time to disease progression and OS. Men with an increase in tumour volume and increase in PSA early in treatment (6 weeks) had shorter time to disease progression and OS. Men with early biomarker disease progression were offered alternative treatments early in an attempt to allow the opportunity to allow a more effective potential therapy, if one was available. The study is an analysis of a clinical programme, and was not a prospective trial. As such, there are potential biases that could influence results. Hence, while the study is encouraging for the use of early response biomarkers to guide better treatment decisions, this must be validated in a well-designed clinical trial.

NCCN Guidelines® Insights: Prostate Cancer, Version 1.2023.

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, recurrent, and metastatic disease. The NCCN Prostate Cancer Panel meets annually to reevaluate and update their recommendations based on new clinical data and input from within NCCN Member Institutions and from external entities. These NCCN Guidelines Insights summarizes much of the panel's discussions for the 4.2022 and 1.2023 updates to the guidelines regarding systemic therapy for metastatic prostate cancer.

Range-Bounded Adaptive Therapy in Metastatic Prostate Cancer.

Adaptive therapy with abiraterone acetate (AA), whereby treatment is cycled on and off, has been presented as an alternative to continuous therapy for metastatic castration resistant prostate cancer (mCRPC). It is hypothesized that cycling through treatment allows sensitive cells to competitively suppress resistant cells, thereby increasing the amount of time that treatment is effective. It has been proposed that there exists a subset of patients for whom this competition can be enhanced through slight modifications. Here, we investigate how adaptive AA can be modified to extend time to progression using a simple mathematical model of stem cell, non-stem cell, and prostate-specific antigen (PSA) dynamics. The model is calibrated to longitudinal PSA data from 16 mCRPC patients undergoing adaptive AA in a pilot clinical study at Moffitt Cancer Center. Model parameters are then used to simulate range-bounded adaptive therapy (RBAT) whereby treatment is modulated to maintain PSA levels between pre-determined patient-specific bounds. Model simulations of RBAT are compared to the clinically applied adaptive therapy and show that RBAT can further extend time to progression, while reducing the cumulative dose patients received in 11/16 patients. Simulations also show that the cumulative dose can be reduced by up to 40% under RBAT. Through small modifications to the conventional adaptive therapy design, our study demonstrates that RBAT offers the opportunity to improve patient care, particularly in those patients who do not respond well to conventional adaptive therapy.

New S3 guideline prostate cancer 2021 (version6.2)-What has changed in advanced prostate cancer?

There have been numerous new findings from clinical trials in recent years regarding the treatment of metastatic hormone-sensitive or castration-resistant prostate cancer. The newly approved treatment options make therapy planning and therapy sequencing more challenging. In addition, local therapy of metastatic prostate cancer is becoming increasingly important. In the new German guidelines on prostate cancer (version6.2, October 2021), new developments in the recommendations for the treatment of mHSPC and mCRPC were implemented, and their most important resulting recommendations for the clinical practice are presented in this review.

A Treatment Paradigm Shift: Targeted Radionuclide Therapies for Metastatic Castrate Resistant Prostate Cancer

Simple SummaryMetastatic prostate cancer has traditionally been treated with a combination of hormonal and chemotherapy regimens. With the recent FDA approval of targeted radionuclide therapeutics, there is now a new class of therapy that is routinely available to patients and clinicians. This review explores the most commonly studied therapeutic radiopharmaceuticals and their appropriate use and contraindications. Additionally, we detail how these therapeutic radiopharmaceuticals can fit into the common medical oncology practice and future directions of this field of medicine.The recent approval of 177Lu PSMA-617 (Pluvicto®) by the United States Food and Drug Administration (FDA) is the culmination of decades of work in advancing the field of targeted radionuclide therapy for metastatic prostate cancer. 177Lu PSMA-617, along with the bone specific radiotherapeutic agent, 223RaCl2 (Xofigo®), are now commonly used in routine clinical care as a tertiary line of therapy for men with metastatic castrate resistant prostate cancer and for osseus metastatic disease respectively. While these radiopharmaceuticals are changing how metastatic prostate cancer is classified and treated, there is relatively little guidance to the practitioner and patient as to how best utilize these therapies, especially in conjunction with other more well-established regimens including hormonal, immunologic, and chemotherapeutic agents. This review article will go into detail about the mechanism and effectiveness of these radiopharmaceuticals and less well-known classes of targeted radionuclide radiopharmaceuticals including alpha emitting prostate specific membrane antigen (PSMA)-, gastrin-releasing peptide receptor (GRPR)-, and somatostatin targeted radionuclide therapeutics. Additionally, a thorough discussion of the clinical approach of these agents is included and required futures studies.

Radiotherapy to the Primary Tumor: The First Step of a Tailored Therapy in Metastatic Prostate Cancer

Prostate cancer is the first most frequent cancer in men worldwide, with over 250,000 estimated new cases diagnosed in 2021 [...]

Identification of the α2 chain of interleukin-13 receptor as a potential biomarker for predicting castration resistance of prostate cancer using patient-derived xenograft models.

Several treatment strategies use upfront chemotherapy or androgen receptor axis-targeting therapies for metastatic prostate cancer. However, there are no useful biomarkers for selecting appropriate patients who urgently require these treatments. Novel patient-derived xenograft (PDX) castration-sensitive and -resistant models were established and gene expression patterns were comprehensively compared. The function of a gene highly expressed in the castration-resistant models was evaluated by its overexpression in LNCaP prostate cancer cells. Protein expression in the tumors and serum of patients was examined by immunohistochemistry and ELISA, and correlations with castration resistance were analyzed. Expression of the α2 chain of interleukin-13 receptor (IL13Rα2) was higher in castration-resistant PDX tumors. LNCaP cells overexpressing IL13Rα2 acquired castration resistance in vitro and in vivo. In tissue samples, IL13Rα2 expression levels were significantly associated with castration-resistant progression (p < 0.05). In serum samples, IL13Rα2 levels could be measured in 5 of 28 (18%) castration-resistant prostate cancer patients. IL13Rα2 was highly expressed in castration-resistant prostate cancer PDX models and was associated with the castration resistance of prostate cancer cells. It might be a potential tissue and serum biomarker for predicting castration resistance in prostate cancer patients.

Role of multidisciplinary team meetings in implementation of chemohormonal therapy in metastatic prostate cancer in daily practice.

The recommended treatment for a subset of patients with metastatic prostate cancer (mPC) changed from androgen deprivation therapy (ADT) to combinations with chemotherapy such as docetaxel. Implementation of new evidence from trials is however complex and challenging. We investigated the effect of multidisciplinary team meetings (MDTs) on adopting the newest emerging combination therapy in patients with mPC and assessed the overall survival of chemohormonal therapy in a real-world setting. All mPC patients diagnosed between October 2015 and April 2016 in the Netherlands were identified from the population-based Netherlands Cancer Registry (n = 962). Logistic regression analyses were performed to examine the role of patient- and tumor characteristics, with special emphasis on MDTs, on receiving chemohormonal therapy versus ADT monotherapy. Kaplan-Meier survival curves were used to assess overall survival (OS). As many patients received ADT monotherapy as chemohormonal therapy (both n = 452). Being discussed in a MDT as patient, younger age, less comorbidities, a better performance status and high-volume disease were significantly associated with receiving chemohormonal therapy compared to ADT monotherapy. After adjustment for these factors, the presence of a MDT was independently associated with the administration of chemohormonal therapy (OR 2.77, 95% CI 1.68-4.59). The 2-year OS was 82.1% (95% CI: 78.5-85.6%) for patients receiving chemohormonal therapy and 59.9% (95% CI: 55.4-64.4%) for patients receiving ADT monotherapy. Being discussed in a MDT is independently associated with the administration of chemohormonal therapy in this group of patients with mPC. This supports the hypothesis that implementation of innovative treatment options is facilitated by an organizational structure with MDTs.

Polymorphism of 3β-Hydroxysteroid Dehydrogenase-1 in patients with prostate cancer in middle Euphrates of Iraq

Androgens play critical roles in prostate carcinogenesis as well as prostate cancer progression. Androgen-deprivation therapy (ADT), which reduces testosterone production and inhibits androgen action in prostate cancer cells, has been the criterion standard therapy for metastatic prostate cancer (1). Although initially most prostate cancers respond well to ADT, most patients eventually progress to castration-resistant prostate cancer (CRPC), which is mainly thought to be because androgen receptor reactivation is induced by several mechanisms. One of those mechanisms have been identified to be intratumoral androgen synthesis mostly from adrenal precursor steroids and at least in part due to de novo synthesis from cholesterol which is supported by increased expression of several genes encoding steroidogenic enzymes including HSD3B, HSD17B, and SRD5A in CRPC. Among them, HSD3B1 gene encodes 3β-hydroxysteroid dehydrogenase-1, which is mainly expressed in peripheral tissues including the prostate (another isoform, 3β-hydroxysteroid dehydrogenase-2 was mainly expressed in adrenal gland and gonad in human) and is a rate-limiting enzyme required for all pathways of dihydrotestosterone synthesis. Genetic polymorphism in HSD3B1 encoding 3β-hydroxysteroid dehydrogenase-1 has been shown to be associated with oncological outcome for prostate cancer. This study to investigate the significance of missense polymorphism in HSD3B1 gene (rs1047303) among men with prostate cancer.

Analysis of innovative clinical developments in the field of therapy for metastatic prostate cancer: bright results of the ASCO Congress-2022

Introduction. Prostate cancer (PC), according to the results for 2019, is the second most frequently diagnosed malignant tumor in men living in the Russian Federation. There is a significant proportion of patients with advanced (III-IV stages) of prostate cancer - up to 50 %, while metastatic cancer accounts for up to 18.1 % of patients. Popularization in the Moscow City Healthcare clinical practice of innovative technologies for managing patients with metastatic castration-resistant prostate cancer (mCRPC) directly meets the goals and objectives of the Federal project aimed at increasing the life expectancy of cancer patients.&#x0D; Materials and methods. The article reviews the results of clinical developments in the field of mCRPC treatment presented at The ASCO Annual Meeting, June 3-7, 2022: VISION sub-studies, TheraP study, study of the prognostic role of circulating tumor DNA (ctDNA) in the early choice of a strategy for the use of abiraterone or enzalutamide in patients with initial mCRPC - treatment naïve - status.&#x0D; Results and discussion. The volume of clinical information on the results of theranostic antitumor radiation technologies implemented with the participation of prostate-specific membrane antigen (hereinafter referred to as PSMA) is growing rapidly. PSMA - mediated radio-imaging is considered as a potentially effective tool for selecting patients who are sensitive to specific therapy. When studying radionuclide therapy mediated by a ligand to PSMA (PSMA-L), the main efforts are focused on determining the optimal regimens for its clinical application. The possibility of expanding the current indications for prescribing 177Lu-PSMA-617 to patients with prostate cancer at an earlier stage is also being studied. Until final results are obtained from clinical trials that provide clear answers to open questions regarding various aspects of the application of innovative PSMA - mediated theranostic technologies, it remains very important to reach an expert consensus, within the framework of an exchange of opinions, re arding their appropriate use in various clinical situations.

Clinical Features and Body Composition in Men with Hormone-Sensitive Metastatic Prostate Cancer: A Pilot Study Examining Differences by Race.

Black men treated with frontline therapies for metastatic prostate cancer (MPC) show better clinical outcomes than non-Black men receiving similar treatments. Variations in body composition may contribute to these findings. However, preliminary data are required to support this concept. We conducted a retrospective cohort study for all men with MPC evaluated at our center over a 4-year period, collecting demographic and clinical data (N = 74). Of these, 55 men had diagnostic computed tomography images to quantify adipose tissue and skeletal muscle, specifically sarcopenia and myosteatosis. Nineteen men had repeat imaging to explore changes over time. Frequencies, medians, interquartile ranges, and time to event analyses (hazard ratios (HR); confidence interval (CI)) are presented, stratified by race. Overall, 49% (n = 27) of men had sarcopenia, 49% (n = 27) had myosteatosis, and 29% (n = 16) had sarcopenia and myosteatosis simultaneously. No significant relationship between body mass index (Log-rank p=0.86; HR: 1.05, 95% CI: 0.45–2.49) or sarcopenia (Log-rankp=0.92; HR: 1.01, 95% CI: 0.46–2.19) and overall survival was observed. However, the presence of myosteatosis at diagnosis was associated with decreased overall survival (Log-rank p=0.09; HR: 2.34, 95% CI: 1.05–5.23), with more pronounced (statistically nonsignificant) negative associations for Black (HR: 4.39, 95% CI: 0.92–21.1, p=0.06) versus non-Black men (HR: 1.89, 95% CI: 0.79–4.54, p=0.16). Over the median 12.5 months between imaging, the median decline in skeletal muscle was 4% for all men. Black men displayed a greater propensity to gain more adipose tissue than non-Black men, specifically subcutaneous (p=0.01). Because of the potential for Type II errors in this pilot, future studies should seek to further evaluate the implications of body composition on outcomes. This will require larger, adequately powered investigations with diverse patient representation.

Augmented alpha-beta PSMA radioligand therapy in metastatic prostate cancer: Analysis of prognostic factors for survival.

e17025 Background: PSMA-targeted radioligand therapy (PRLT) using the alpha-emitter Ac-225 PSMA-617 is effective in metastatic prostate cancer progressing after beta-emitter-based PRLT using Lu-177 PSMA-617, and in the presence of diffuse bone marrow metastases. Xerostomia is a dose-limiting factor in PRLT using Ac-225. Augmented Alpha-Beta PRLT is a concept of concomitantly administering Lu-177 and Ac-225 PSMA in lower activities, as a trade-off between efficacy and the dose-limiting toxicity, i.e., xerostomia. The objective of this study was to compare overall survival (OS), progression-free survival (PFS), and incidence of xerostomia among metastatic prostate cancer patients who received Ac-225 PSMA-617 augmentation in the initial phase of Lu-177 PSMA-617 RLT compared to those who received it in the late phase. Initial phase is defined as first two cycles of PSMA radioligand therapy (PRLT) vs late phase as after two cycles. We also examined prognostic factors associated with OS and PFS. Methods: Kaplan Meier method was used to examine survival curves and log-rank tests were conducted to examine differences in survival by groups. Cox Proportional Hazard (CPH) model was used to examine the impact of bone marrow and visceral metastasis and age on OS and PFS. Progression was defined as an increase of ≥ 25% in prostate-specific antigen (PSA) levels. Results: 68 patients who received Ac-225 PSMA-617 by itself, or Ac-225 PSMA-617 augmentation to Lu-PSMA-617 were included in the analysis. Out of these, 15 received early augmentation, 50 received late augmentation, and 3 received Ac-225 PSMA-617 alone. Of these, 48 experienced cancer progression and 21 died due to cancer progression. Median OS was 47 months and PFS was 11 months. Those who received early augmentation had significantly better PFS (median PFS not reached during study period) compared to those who received late augmentation (median PFS: 9 months) (p = 0.02). Early augmentation was associated with lower likelihood of xerostomia (p = 0.09). CPH model suggested that visceral or bone marrow metastasis were associated with significantly worse prognosis for PFS (p = 0.04). Conclusions: In patients progressing after Lu-177 PSMA radioligand therapy and those with diffuse bone-marrow metastases, an earlier augmentation with Ac-225 PSMA-617 is associated with better PFS and lower side effects such as xerostomia. Having visceral or bone marrow metastasis is a poor prognostic indicator for PFS in augmented alpha-beta PSMA radioligand therapy.

Predictors of overall survival among Black South African men treated with androgen-deprivation therapy for metastatic prostate cancer.

5046 Background: Men in sub-Saharan Africa (SSA) are disproportionately affected by prostate cancer (PCa), and many have metastatic disease (mPCA) at presentation. In SSA, androgen deprivation therapy (ADT) is the first-line treatment for mPCa, and often the only available therapy. Treatment failure and death is common. We identified predictors of overall survival (OS) in Black South African (SA) men with mPCa on ADT. Methods: We performed a retrospective analysis of prospectively gathered data from men diagnosed with mPCA (3/22/2016 - 10/30/2020) at Chris Hani Baragwanath Hospital in Johannesburg, which was also a study site for the concurrent Men of African Descent and Carcinoma of the Prostate study. We included men with mPCA treated with ADT (received at least 1 dose of luteinizing hormone-releasing hormone agonist and/or had surgical castration), who had ≥1 PSA level drawn ≥12 weeks after ADT start. OS was defined from ADT start to death. PSA progression (PSA-P) definition was adapted from PCWG 3. Cox regression models were used to identify predictors of OS. PSA-P was treated as a time-dependent covariate. Results: Of 200 men with mPCa, we excluded 6 who did not receive ADT and 41 without sufficient data for PSA-P analysis. Of 153 men, 26.8% were &lt;65 years old and 12% had a family history of PCa. Median PSA at diagnosis was 71.5 ng/mL (interquartile range (IQR) 20.7-432.6), median alkaline phosphatase level (ALP) 108 IU/L (79-224) and median hemoglobin (Hb) 13 g/dL (IQR 10-15). Median PSA nadir was 2.8 ng/mL (IQR 0.55-17.93). The rate of PSA-P at 1- and 2-years was 12.1% [95%CI 5.9-17.8] and 37.5% [95%CI 26.1-47.2]. The median follow-up was 2.75 years, and the 3-year OS was 61.9% [95%CI 52.7-72.6]. Cox proportional hazard ratio (HR) models of risk factors for OS are shown in Table 1. PSA-P was a strong predictor of OS. Men with PSA nadir &gt;4ng/mL after ADT start had a HR for death of 3.77 [1.86-7.62]. Men with ALP &gt;150 IU/L and those with Hb &lt;13.5g/dL at diagnosis were also at higher risk for death (HR 3.09 [1.64-5.83] and HR 2.00 [1.28-6.56] respectively). Conclusions: Among Black men in SA treated with ADT for mPCA, PSA-P strongly predicts OS. In this cohort, high ALP and anemia at diagnosis, and PSA nadir &gt;4ng/mL after ADT start are associated with higher risk for death. These factors can be used identify high risk men with mPCA, for whom early treatment escalation to chemotherapy should be considered. [Table: see text]

Abstract IA015: Exploring how competition can be leveraged to improve adaptive therapy in metastatic prostate cancer

Abstract Prostate cancer remains the most prevalent cancer in men in the US. While continuous first-line hormone treatment at maximum tolerable dose is the standard of care, continuous treatment often selects for the resistant phenotypes resulting in castration resistant disease. Second-line hormone therapy options, such as abiraterone acetate (AA), have been proven effective for metastatic castration resistant prostate cancer (mCRPC). Adaptive AA, whereby treatment is cycled on and off using patient-specific treatment triggers, has been shown to be effective at reducing toxicity and prolonging time to progression. It is hypothesized that cycling through treatment allows sensitive cells to competitively suppress resistant cells, thereby increasing the amount of time that treatment is effective. It has been proposed that there exists a subset of patients for which this competition can be enhanced through slight modifications to adaptive AA. Here, we investigate this by calibrating a simple mathematical model to longitudinal prostate-specific antigen data from 16 mCRPC patients undergoing adaptive AA. Model parameters are used to simulate modified adaptive therapy and compare against conventional adaptive therapy. Model simulations show that modified adaptive therapy can extend time to progression, while reducing the cumulative dose patients receive. This is a promising first step in improving patient care, particularly in those patients who do not respond well to conventional adaptive therapy. Citation Format: Renee Brady-Nicholls, Heiko Enderling. Exploring how competition can be leveraged to improve adaptive therapy in metastatic prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA015.

Assessment of salivary gland function after 177Lu-PSMA radioligand therapy: Current concepts in imaging and management

Prostate specific membrane antigen (PSMA) is a transmembrane protein that is highly expressed on prostate epithelial cells and is strongly upregulated in prostate cancer. Radioligand therapy using beta-emitting Lutetium-177 (177Lu)-labeled-PSMA-617, a radiolabeled small molecule, has gained attention as a novel targeted therapy for metastatic prostate cancer, given its high affinity and long tumor retention, and rapid blood pool clearance. In March 2022, the United States Food and Drug administration has granted approval to the targeted 177Lu-PSMA-617 therapy for treatment of patients with PSMA-positive metastatic castration resistant prostate cancer, who have been previously treated with an androgen-receptor pathway inhibitor and taxane-based chemotherapy. Studies have demonstrated the adverse effects of this treatment, mainly encountered due to radiation exposure to non-target tissues. Salivary glands show high PSMA-ligand uptake and receive increased radiation dose secondary to accumulation of 177Lu-PSMA-617. This predisposes the glands to radiation-mediated toxicity. The exact mechanism, scope and severity of radiation-mediated salivary gland toxicity are not well understood, however, the strategies for its prevention and treatment are under evaluation. This review will focus on the current knowledge about salivary gland impairment post 177Lu labeled PSMA-based radioligand therapies, diagnostic methodologies, and imaging with emphasis on salivary gland scintigraphy. The preventive strategies and known treatment options would also be briefly highlighted.

PD46-03 METASTASIS PRONE GENES IN PROSTATE CANCER REVEALED BY TARGETED SEQUENCING

You have accessJournal of UrologyCME1 May 2022PD46-03 METASTASIS PRONE GENES IN PROSTATE CANCER REVEALED BY TARGETED SEQUENCING Seung-hwan Jeong, Jang Hee Han, Hyeong-Dong Yuk, Chang-Wook Jeong, Hyeon-Hoe Kim, Ja-Hyeon Ku, and Cheol Kwak Seung-hwan JeongSeung-hwan Jeong More articles by this author , Jang Hee HanJang Hee Han More articles by this author , Hyeong-Dong YukHyeong-Dong Yuk More articles by this author , Chang-Wook JeongChang-Wook Jeong More articles by this author , Hyeon-Hoe KimHyeon-Hoe Kim More articles by this author , Ja-Hyeon KuJa-Hyeon Ku More articles by this author , and Cheol KwakCheol Kwak More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002614.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Tremendous information acquired by NGS improved oncogenomics to defining cancer-related genes including oncogenes and tumor suppressor genes facilitating detailed diagnosis, enhanced anticipation of the prognosis, and precision medicine for each patient. In Seoul National University Hospital, targeted sequencing was designed to be suitable for multiple cancers, named FIRST-cancer panel version 3.2.2. In most cases, sequenced samples were prostates which were obtained from radical prostatectomy. However, in several patients, sequenced tissues were obtained from metastatic site. Notably, we found that there are significant differences of genetic aberrations shared in prostate and metastatic sites which inspire the genetic drive required on metastasis to be targeted for the further treatments. METHODS: Targeted sequencing data were obtained from 93 prostate cancer patients. Tissue origins of each cases were identified and classified into two groups, prostate or metastatic sites. The pooled data in each group was analysed using OncoPrint through cBioportal. Genetic aberrations were comparatively analysed to find significant genes representing each groups. RESULTS: In total of 93 patients underwent targeted-sequencing using FIRST-cancer panel version 3.2.2, 80 cases of NGS were perform on the samples from prostate (Primary group) and 13 cases were from distant metastasis site (Mets group). To visualize diverse genetic aberration, OncoPrint was drawn through cBioPortal. The genes were displayed in descending order of mutation frequencies in the two groups.In Primary group FOXA1, RB1, BRCA2, TP53, and SPOP were top 5 genes which were altered most frequently. However in Mets group FANCA, TMPRSS, ERG, TP53, and PTEN were top 5 genes of most altered. In the proportional analysis of each groups, contributing genes for metastasis were identified as UGT1A1, NRG1, and FANCA. When survival analysis were conducted on TCGA data, UGT1A1 or NRG1 mutated patients showed poor overall survival. CONCLUSIONS: Primary and metastatic prostate cancers contain differently shared genetic aberrations. In metastatic prostate cancer, UGT1A1, NRG1, and FANCA were distinctively mutated compared with primary prostate cancer, suggesting promising target for metastatic prostate cancer therapy. Source of Funding: This research was supported by a Basic Science Research Program through National Research Foundation of Korea (NRF), funded by the Ministry of Education (NRF-2018R1D1A1B07041191) and by Seoul National University Hospital (0320210060) © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e788 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Seung-hwan Jeong More articles by this author Jang Hee Han More articles by this author Hyeong-Dong Yuk More articles by this author Chang-Wook Jeong More articles by this author Hyeon-Hoe Kim More articles by this author Ja-Hyeon Ku More articles by this author Cheol Kwak More articles by this author Expand All Advertisement PDF DownloadLoading ...

The emerging role of cross-resistance between taxanes and AR-targeting therapy in metastatic prostate cancer

Background: To date, the number of prostate cancer ranked first among newly diagnosed malignant tumors in men from multiple countries. Localized prostate cancer could be controlled by curative therapy. However, for patients with metastatic prostate cancer (mPC), the prognosis is poor. As among first-line treatments of systemic therapies for mPC, docetaxel and androgen receptor (AR)-targeted therapies have been widely used. However, mPC patients inevitably developed resistance to the current therapy. More importantly, there is a cross-resistance between docetaxel-based chemotherapy and AR-targeting therapy during the treatment process, which could impair the overall survival benefits without proper administration. Objective: Therefore, it is urgent to elucidate the mechanism of cross-resistance and explore the optimal sequential strategy. Methods: Here, in this review, we systematically reviewed and summarised the updated literature on clinical evidence and mechanistic research of treatment resistance in mPC. Results: Emerging evidence indicated that AR splice variants, AR overexpression or mutations, AR nuclear translocation, as well as AR signaling reactivation collectively contributed to the cross-resistance. With the current understanding of cross-resistance, multiple solutions are promising for improving the benefits, including refining the sequencing of available therapies for mPC, in combination with potential targeted inhibitors or immune checkpoint inhibitors. Further studies are needed to explore the combination of emerging strategies and eventually control the progression of prostate cancer. Conclusions: This review defined the mutual and unique resistant mechanism of these treatments, which might help to focus and accelerate therapeutic research that may ultimately improve clinical outcomes for patients with prostate cancer. Level of evidence: Not applicable

Treatment outcome and identification of factors influencing overall survival after Lu-177-PSMA-617 radioligand therapy in metastatic prostate cancer

To examine the clinical benefit of Lu-177-PSMA-617 radioligand therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). Between November 2014 and December 2018, a total of 56 consecutive patients (median age 69.5 years; range 55-84 years) with mCRPC were included in this retrospective analysis. Patients received between 1 and 4 therapy cycles with a mean activity of 6.8 GBq per cycle. Biochemical response was evaluated using Prostate Cancer Working Group Criteria 3 (PCWG 3). Survival was assessed using Kaplan-Meier estimates and Cox proportional hazards regression analysis. This retrospective study was approved by the local ethics committee. A total of 139 treatment cycles with Lu-177-PSMA-617 were performed. A decline of 50% or more of prostate-specific antigen (PSA) level occurred in 54% and a PSA decline of any amount in 65% of patients. The estimated median overall survival (OS) was 16 months, in the chemotherapy subgroup 14 months. A longer OS was associated with a PSA-decline ≥50%, more than 2 cycles of therapy, cumulative activity >15 GBq and an initial alkaline phosphatase ≤ 220 [U/l]. These identified predictors remained significant on uni- and multivariate Cox regression analysis. Moreover, 40% of the patients who were non-responders after the first therapy cycle turned into responders after the second one. PSA-decline ≥50%, a cumulative activity >15 GBq and an initial alkaline phosphatase ≤ 220 [U/l] were identified as key predictors of prolonged OS in patients with mCRPC. In contrast rapid clinical deterioration mostly due to skeletal carcinomatosis resulted in early treatment failure.

Facility-Level Variation in Use of Locoregional Therapy for Metastatic Prostate Cancer.

We sought to understand patient- and institution-level factors associated with use of locoregional therapy for newly diagnosed metastatic prostate cancer in the era before the availability of evidence supporting its efficacy. We queried the National Cancer Database to identify patients diagnosed with metastatic prostate adenocarcinoma (stage M1) between 2004 and 2017. We assessed patient factors associated with definitive local therapy with radiotherapy or radical prostatectomy using multilevel logistic regression accounting for clustering within institutions. We further characterized trends in facility-level use and examined institutional factors associated with utilization. We identified 35,933 patients with M1 prostate cancer at 1,188 facilities. A total of 4,146 patients (11.5%) received local therapy for M1 disease (radiation therapy in 3,378 and radical prostatectomy in 768). Use of local treatment was concentrated among a smaller number of facilities: 50% of all local therapy was delivered at 161 facilities (14% of total). At the patient level, uninsured status (OR 0.62, 95% CI 0.49-0.79, p <0.01) and high comorbidity (Charlson-Deyo score, OR 0.39, 95% CI 0.26-0.6, p <0.01) were associated with lower odds of local therapy. High-utilizing facilities (top quartile) were more commonly community centers (OR 1.76, 95% CI 10.7-2.95, p <0.01) and differed by geographic region (South Atlantic vs West South Central region: OR 0.48, 95% CI 0.25-0.88, p=0.02). In the period before locoregional therapy was supported by clinical practice guidelines, locoregional therapy use varied significantly at the facility level and was driven by a smaller number of high-utilizing facilities. These findings can contextualize expected increase in the use of local therapy for metastatic prostate cancer.