Diagnosis Of Castration-resistant Prostate Cancer Research Articles

Radiographic Progression at Castration-Resistant Prostate Cancer Diagnosis: A Prognostic Indicator of Metastatic Hormone-Sensitive Prostate Cancer

BackgroundThe critical role of radiographic assessment at the time of castration-resistant prostate cancer (CRPC) diagnosis is underscored by this study. We performed a retrospective analysis of radiographic changes in metastasis from the time of diagnosis of metastatic hormone-sensitive prostate cancer (mHSPC) to CRPC diagnosis. We also explored its impact on prognosis post-CRPC. Materials and MethodsWe retrospectively analyzed 98 men who underwent radiographic examinations (bone scans and computed tomography [CT]) at the time of CRPC diagnosis. When radiographic studies demonstrated progression at CRPC diagnosis, patients were assigned to the radiographic progressive disease (rPD) group. The remaining patients were placed in the "non-rPD" group. The overall survival (OS) post-CRPC was compared between the 2 groups. ResultsThe median OS post-CRPC was significantly shorter in the rPD group (n = 50) compared to the non-rPD group (n = 48) (32 months vs. not reached, P = .0124). Multivariate analysis showed that radiographic progression and shorter time to CRPC were associated with a shorter OS post-CRPC (hazard ratio [HR] = 3.14; 95% confidence interval [CI], 1.21-8.12, P = .019). ConclusionRadiographic progression at the point of CRPC diagnosis independently predicts a shorter OS post-CRPC in patients with mHSPC. Therefore, assessing radiographic changes at the time of CRPC diagnosis could be instrumental in managing CRPC in patients with mHSPC.

A Novel DNA Aptamer Probe Recognizing Castration Resistant Prostate Cancer in vitro and in vivo Based on Cell-SELEX.

Early recognition of castration-resistant state is of significance for timely adjustment of treatment regimens and improvement of prognosis. This study aims to screen new aptamers CRda8 and CRda21 which recognize castration resistant prostate cancer (CRPC) cells with high affinity and specificity by SELEX technology. The enrichment of specific aptamer candidates was monitored by flow cytometric analysis. The affinity and specificity of aptamer candidates were evaluated by flow cytometry and immunofluorescence assay. MR imaging of CRda21-conjugated polyethylene glycol (PEG)-Fe3O4 nanoparticles to CRPC was further explored in vivo. Both aptamers showed high specificity to target cells with dissociation constants in the nanomolar range, and did not recognize other tested cells. The staining of clinical tissue sections with fluorescent dye labeled aptamers showed that sections from CRPC exhibited stronger fluorescence while sections from benign prostatic hyperplasia and androgen dependent prostate cancer did not exhibit notable fluorescence. In vivo MRI demonstrated that CRda21-conjugated PEG-Fe3O4 had good affinity to CRPC and produced strong T2WI signal intensity reduction distinguished from peritumoral tissue. The high affinity and specificity of CRda8 and CRda21 make the aptamer hold potential for early recognition of castration-resistant state and diagnosis of CRPC at the cellular level.

Longitudinal change in castration-resistant prostate cancer biomarker AST/ALT ratio reflects tumor progression

We investigated whether aspartate transaminase (AST)-to-alanine aminotransferase (ALT) ratio and its change during the course of treatment in castration-resistant prostate cancer (CRPC) patients is associated with tumor condition and lethality. Clinical data from 130 CRPC patients were retrospectively evaluated. AST/ALT ratios at the time of prostate cancer (PC) diagnosis, androgen deprivation therapy (ADT), CRPC diagnosis, and the final follow-up examination after CRPC treatment were calculated for each. The prognostic capabilities of the AST/ALT ratio for overall survival (OS) were analyzed by use of the Kaplan–Meier method and Cox hazard models. The median AST/ALT ratio at PC diagnosis was 1.517 and the optimal value predicting lethality defined by the receiver operating curve was 1.467. The AST/ALT ratio decreased once during ADT and then elevated in a stepwise manner with cancer progression. In surviving patients, the median AST/ALT ratio at the time of PC diagnosis was 1.423, which did not change longitudinally, whereas that in patients later deceased was significantly higher (1.620) and further elevated after CRPC diagnosis. Kaplan–Meier curves indicated significantly worse OS in patients with an AST/ALT ratio ≥ 1.467, which was confirmed by multivariate analysis. These findings indicate AST/ALT ratio as a prognostic biomarker for CRPC with longitudinal changes reflecting tumor progression.

Development and Validation of a Tool to Identify Patients Diagnosed With Castration-Resistant Prostate Cancer.

Several novel therapies for castration-resistant prostate cancer (CRPC) have been approved with randomized phase III studies with continuing observational research either planned or ongoing. Accurately identifying patients with CRPC in electronic health care data is critical for quality observational research, resource allocation, and quality improvement. Previous work in this area has relied on either structured laboratory results and medication data or natural language processing (NLP) methods. However, a computable phenotype using both structured data and NLP identifies these patients with more accuracy. The Corporate Data Warehouse (CDW) of the Veterans Health Administration (VHA) was used to collect PCa diagnoses, prostate-specific antigen test results, and information regarding patient characteristics and medication use. The final system used for validation and subsequent analysis combined the NLP system and an algorithm of structured laboratory and medication data to identify patients as being diagnosed with CRPC. Patients with both a documented diagnosis of CRPC and a documented diagnosis of metastatic PCa were classified as having mCRPC by this system. Among 1.2 million veterans with PCa, the International Classification of Diseases (ICD)-10 diagnosis code for CRPC (Z19.2) identifies 3,791 patients from 2016 when the code was created until 2022, compared with the combined algorithm which identifies 14,103, 10,312 more than ICD-10 codes alone, from 2016 to 2022. The combined algorithm showed a sensitivity of 97.9% and a specificity of 99.2%. ICD-10 codes proved to be insufficient for capturing CRPC in the VHA CDW data. Using both structured and unstructured data identified more than double the number of patients compared with ICD-10 codes alone. Application of this combined approach drastically improved identification of real-world patients and enables high-quality observational research in mCRPC.

Abstract B020: BCL2 expression is enriched in AR-independent advanced prostate cancer

Abstract Background The widespread use of highly potent androgen receptor (AR) inhibitors has led to an increasing emergence of AR-independent castration-resistant prostate cancer (CRPC). AR independence, typically driven by loss of AR expression and/or trans-differentiation to a neuroendocrine or basal phenotype, lacks effective therapeutic strategies. The anti-apoptotic protein BCL2 is upregulated in neuroendocrine tumours and has been proposed as a therapeutic target for this subset of advanced prostate cancers. Objective To characterise AR expression in advanced PC, to evaluate its association with BCL2, to elucidate their clinical significance, and to explore whether BCL2 may represent a valid therapeutic target and/or biomarker. Methods AR and BCL2 expression were immunohistochemically scored in two independent CRPC cohorts (431 biopsies from 247 patients), including 62 matched same-patient castration-sensitive PC (CSPC) biopsies. Scores were associated with retrospectively collected clinical data including overall survival (OS) and response to AR-targeting therapy. BCL2 protein expression was also determined in 28 primary prostate samples (19 patients). Transcriptome data from two independent CRPC cohorts were analysed, including for associations between BCL2 expression and gene expression signatures. A patient-derived xenograft-organoid (PDX-O) CRPC model with high expression of BCL2 was treated with multiple BH3 mimetics. Results and limitations We demonstrate that AR protein loss emerges with castration resistance and occurs in subset of metastatic CRPC (mCRPC) (5%) associating with worse OS (51 vs 18 months from CRPC diagnosis, hazard ratio [HR] 5.52 [2.83-10.78], p<0.001). BCL2 protein expression is enriched in AR-negative mCRPC (p<0.001), associating with worse OS (53 vs 19 months from CRPC diagnosis, HR 2.80 [1.40-5.57], p=0.002) and resistance to AR-targeting therapy (≥50% PSA response: 48% vs 13%), irrespective of AR expression status. BCL2 mRNA expression associates with several key signalling pathways known to promote stemness and lineage plasticity, including EMT and IL6/JAK/STAT3. Furthermore, BCL2 is enriched in basal prostate cells, whose expression profile has been linked with aggressive subtypes of mCRPC, including small cell neuroendocrine CPRC. We show that a high BCL2-expressing PDX-O is resistant to BCL2 inhibition, with functional redundancy between the anti-apoptotic BCL2 family proteins. BCLXL and MCL1 are highly expressed in BCL2-positive mCRPC and may drive resistance to BCL2 targeting. Utilising a post-mortem mCRPC biopsy cohort, we show intra-patient heterogeneity in BCL2 expression. These findings highlight the need for combination therapies. Further studies are required to dissect the interaction between AR and BCL2, and to probe the functional role of BCL2 in this subset of mCRPC. Conclusions BCL2-positivity associates with AR-independence, worse OS, and resistance to AR-targeting in CRPC. Combination strategies are required to optimise response to BCL2 inhibition and to combat heterogeneity. Citation Format: Daniel Westaby, Juan M. Jimenez-Vacas, Ines Figueiredo, Claire Pettinger, Bora Gurel, Denisa Bogdan, Jan Rekowski, Lorenzo Buroni, Antje Neeb, Ruth Riisnaes, Mateus Crespo, Susana Miranda, Ana Ferreira, Daniel Nava Rodrigues, George Seed, Claudia Bertan, Maria de los Dolores Fenor de la Maza, Christina Guo, Juliet Carmichael, Rafael Grochot, Khobe Chandran, Andreas Varkaris, Steven P. Balk, Wei Yuan, Suzanne Carreira, Peter S. Nelson, Michael Haffner, Eva Corey, Johann de Bono, Adam Sharp. BCL2 expression is enriched in AR-independent advanced prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B020.

Molecular Mechanisms of Noncoding RNA in the Occurrence of Castration-Resistant Prostate Cancer.

Although several therapeutic options have been shown to improve survival of most patients with prostate cancer, progression to castration-refractory state continues to present challenges in clinics and scientific research. As a highly heterogeneous disease entity, the mechanisms of castration-resistant prostate cancer (CRPC) are complicated and arise from multiple factors. Among them, noncoding RNAs (ncRNAs), the untranslated part of the human transcriptome, are closely related to almost all biological regulation, including tumor metabolisms, epigenetic modifications and immune escape, which has encouraged scientists to investigate their role in CRPC. In clinical practice, ncRNAs, especially miRNAs and lncRNAs, may function as potential biomarkers for diagnosis and prognosis of CRPC. Therefore, understanding the molecular biology of CRPC will help boost a shift in the treatment of CRPC patients. In this review, we summarize the recent findings of miRNAs and lncRNAs, discuss their potential functional mechanisms and highlight their clinical application prospects in CRPC.

Administration of radium-223 and the prognosis in Japanese bone metastatic castration-resistant prostate cancer patients: A large database study.

BackgroundThe ALSYMPCA trial revealed radium‐223 (Ra‐223) to be a life‐prolonging agent for bone metastatic castration‐resistant prostate cancer (CRPC). However, only 2.8% of enrolled patients in that clinical trial were Asian, and no Japanese patients were enrolled. Several retrospective studies have been published concerning Japanese bone metastatic CRPC patients receiving Ra‐223. However, no study has yet reported the correlation between Ra‐223 induction and the survival in Japanese bone metastatic CRPC patients. This study investigated the effect of Ra‐223 as a life‐prolonging agent in a large Japanese healthcare fee database.MethodsA total of around 410 000 prostate cancer patients were extracted from this database, and 25 934 were diagnosed with CRPC. In these patients, the age, date of the CRPC diagnosis, date of Ra‐223 induction, and prognosis were analyzed.ResultsA total of 1628 patients received Ra‐223, and 6693 patients were diagnosed with bone metastasis CRPC, with the remaining 17 613 patients diagnosed with CRPC without bone metastasis. The patients who completed six courses of Ra‐223 showed a significantly more favorable overall and cancer‐specific survival than those who received ≤5 courses (p < 0.0001 and p < 0.0001, respectively). For time from CRPC diagnosis date to death, the Ra‐223 induction group showed a significantly more favorable prognosis with regard to both the overall and cancer‐specific survival than the bone metastatic CRPC patients without Ra‐223 (p < 0.0001 and p < 0.0001, respectively).ConclusionsBone metastatic CRPC patients who received Ra‐223 showed a significantly better prognosis than bone metastatic CPRC patients who did not receive Ra‐223.

Testosterone analysis in castrated prostate cancer patients: suitability of the castration cut-off and analytical accuracy of the present-day clinical immunoassays.

Testosterone testing is relevant for evaluating castration adequacy and diagnosis of castration-resistant prostate cancer (PCa). However, the recommended testosterone cut-off of 1.7nmol/L (50ng/dL) to define adequate castration is based on consensus and not validated for the automated immunoassays (AIA) used in today's medical laboratories. Furthermore, appropriate population intervals have not been determined by a state-of-the-art assay. We investigated the analytical suitability of this cut-off and the accuracy of the present-day AIAs for testosterone analysis in castrated PCa patients. Leftover serum from 120 PCa patients castrated with luteinizing hormone-releasing hormone agonists was analysed for testosterone by five methods: Architect i2000 (Abbott), Access (Beckman), Cobas 6000 (Roche), Atellica (Siemens), LC-MS/MS. For all assays, the castration 95th, 97.5th and 99th percentile upper limits were determined. Furthermore, Passing-Bablok regression, mean bias and Spearman's correlation coefficients were compared to the LC-MS/MS method and total error based on biological variation. All castration upper limits, ranging from 0.472nmol/L (LC-MS/MS) to 1.25nmol/L (Access) (95% percentile), were significantly lower than the current castration cut-off (1.7nmol/L). Slopes of Passing-Bablok regressions comparing the AIA with the LC-MS/MS method ranged from 1.4 (Cobas and Atellica) to 3.8 (Access). The Architect showed the highest correlation with LC-MS/MS (ρ=0.58). All AIA failed to meet the desirable total error criterion. These results suggest that a lower general testosterone castration cut-off may be more appropriate in evaluating the adequacy of castration in PCa and that present-day AIA lack analytical accuracy to quantify testosterone levels in castrated PCa.

Humoral response after SARS-CoV-2 mRNA vaccination in patients with prostate cancer using steroids.

ObjectivesThe effect of concomitant steroid use on the antibody response to a SARS-CoV-2 vaccine in patients with prostate cancer (PC) remains unknown. We aimed to evaluate the rates of antispike immunoglobulin G (IgG) antibody response to the BNT162b2 mRNA vaccine in patients with PC using steroids.MethodsThis cross-sectional study conducted from June 21, 2021 to January 5, 2022 included 215 patients with PC who received the second dose of the BNT162b2 mRNA vaccine at least 7 days before the measurement of titers of IgG antibodies against the receptor-binding domain of SARS-CoV-2 spike (S) protein. We compared the rate of anti-SARS-CoV-2 S IgG ≥15 U/mL between patients with or without concomitant steroid use.ResultsOf 215, we identified 33 patients who had concomitant steroid use. Of these, 12 and 21 patients were metastatic castration-sensitive PC and castration-resistant PC (CRPC), respectively. Patients with concomitant steroid use had a significantly lower rate of antibody titer ≥15 U/mL than those without steroid use (82% vs. 95%, P = 0.021). Patients with CRPC with concomitant steroid use (n =21) also had a lower rate of antibody titer ≥15 U/mL (71%) than those without steroid use (93%, P = 0.051), although this was not statistically different. Increased number of systemic treatments administered after diagnosis of CRPC (3 lines or more) were significantly associated with antibody titers <15 U/mL (97% vs. 77%, P <0.001).ConclusionThe humoral response to the BNT162b2 mRNA vaccine was significantly lower in patients with concomitant steroid use. Anti-SARS-CoV-2 S antibody titers were affected by CRPC status, the accumulation of post-CRPC treatments, and steroid use.

Appropriate Patient Status for Ra-223 Treatment in the Treatment Sequence for Castration-resistant Prostate Cancer.

Radium (Ra)-223 is widely used for treating castration-resistant prostate cancer (CRPC) with bone metastasis based on evidence of increased survival and decreased skeletal-related events. However, the timing of Ra-223 use in the treatment sequence of CRPC remains controversial. Therefore, this study aimed to explore the appropriate patient status for Ra-223 use in the CRPC treatment sequence by examining patients treated with Ra-223 from the time of CRPC diagnosis until death. The medical records of 67 CRPC patients with bone metastasis who were treated with Ra-223 at two institutes were retrospectively analysed. The impact of 13 factors from the time of CRPC diagnosis until death was analysed using univariate and multivariate Cox hazard ratio models to evaluate the appropriate patient status for Ra-223 treatment. The median survival time following CRPC diagnosis for all the patient groups was 3.82 years. Univariate analysis identified a higher-than-normal alkaline phosphatase (ALP) level, bone scan indexes ≥2, and prostate-specific antigen (PSA) doubling time <3 months before Ra-223 treatment as predominant adverse prognostic factors. Ra-223 therapy discontinuation was not a significant factor. The survival of CRPC patients with these factors was significantly worse than that of patients without these factors. In the multivariate analysis, a higher-than-normal ALP level at the start of treatment was identified as a poor prognostic factor for mortality. The appropriate patient status for Ra-223 use includes low bone metastasis burden and well-controlled PSA levels.

Elevated serum CEA is associated with liver metastasis and distinctive circulating tumor DNA alterations in patients with castration-resistant prostate cancer.

BackgroundElevated serum carcinoembryonic antigen (CEA) is used to identify “treatment emergent” forms of castration‐resistant prostate cancer (CRPC) such as aggressive variant prostate cancer (AVPC). However, its individual utility as a prognostic marker and the genetic alterations associated with its expression have not been extensively studied in CRPC.MethodsThis study retrospectively analyzed clinical outcomes and circulating tumor DNA profiles in 163 patients with CRPC and elevated or normal serum CEA. These same patients were then classified as AVPC or non‐AVPC and compared to determine the uniqueness of CEA‐associated gene alterations.ResultsPatients with elevated CEA demonstrated higher rates of liver metastasis (37.5% vs. 19.1%, p = 0.02) and decreased median overall survival from CRPC diagnosis (28.7 vs. 73.2 mo, p < 0.0001). In addition, patients with elevated CEA were more likely to harbor copy number amplifications (CNAs) in AR, PIK3CA, MYC, BRAF, CDK6, MET, CCNE1, KIT, RAF1, and KRAS. Based on variant allele frequency we also defined “clonal” single‐nucleotide variants (SNVs) thought to be driving disease progression in each patient and found that CEA expression was negatively correlated with clonal AR SNVs and positively correlated with clonal TP53 SNVs. Of these genetic associations, only the increases in clonal TP53 SNVs and KRAS amplifications were recapitulated among patients with AVPC when compared to patients without AVPC.ConclusionsTogether these findings suggest that CEA expression in CRPC is associated with aggressive clinical behavior and gene alterations distinct from those in AVPC.

Emerging Proteins in CRPC: Functional Roles and Clinical Implications.

Prostate cancer (PCa) is the most common cancer in men in the western world, but the lack of specific and sensitive markers often leads to overtreatment of prostate cancer which eventually develops into castration-resistant prostate cancer (CRPC). Novel protein markers for diagnosis and management of CRPC will be promising. In this review, we systematically summarize and discuss the expression pattern of emerging proteins in tissue, cell lines, and serum when castration-sensitive prostate cancer (CSPC) progresses to CRPC; focus on the proteins involved in CRPC growth, invasion, metastasis, metabolism, and immune microenvironment; summarize the current understanding of the regulatory mechanisms of emerging proteins in CSPC progressed to CRPC at the molecular level; and finally summarize the clinical applications of emerging proteins as diagnostic marker, prognostic marker, predictive marker, and therapeutic marker.

Estrogen receptor β-targeted hypoxia-responsive near-infrared fluorescence probes for prostate cancer study

Aberrant expression of estrogen receptor β (ERβ) and tumor hypoxia have been observed in castration-resistant prostate cancer (CRPC); therefore, hypoxia-responsive labeling of ERβ will be beneficial for the early diagnosis and treatment of CRPC. Herein, we report the first ERβ-targeted hypoxia-responsive near-infrared fluorescent probes, which showed superior ERβ selectivity and favorable optical properties. These two probes exhibited excellent hypoxia responsiveness and specific mitochondrial ERβ imaging ability in CRPC cells. In addition, P1 displayed strong anti-interference ability and good tumor imaging capacity in vivo, contributing to effective diagnosis of CRPC. Mechanistic studies, including high resolution mass spectrometry (HRMS) and density functional theory (DFT) calculations, showed that the introduction of a nitro group quenched the probe fluorescence by inducing a PET effect, while in the hypoxic tumor microenvironment, reduction of the nitro group blocked the PET effect and turned on the probe fluorescence. These novel ERβ-targeted hypoxia-responsive near-infrared fluorescent probes may promote the study of prostate cancer.

Combination of docetaxel versus nonsteroidal antiandrogen with androgen deprivation therapy for high-volume metastatic hormone-sensitive prostate cancer: a propensity score-matched analysis

PurposeThe aim of this study was to investigate the oncologic efficacy of combining docetaxel with androgen deprivation therapy (ADT) versus nonsteroidal antiandrogen (NSAA) with ADT in patients with high-volume metastatic hormone-sensitive prostate cancer (mHSPC) with focus on the effect of sequential therapy in a real-world clinical practice setting.MethodsThe records of 382 patients who harbored high-volume mHSPC, based on the CHAARTED criteria, and had received ADT with either docetaxel (n = 92) or NSAA (bicalutamide) (n = 290) were retrospectively analyzed. The cohorts were matched by one-to-one propensity scores based on patient demographics. Overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), including time to castration-resistant prostate cancer (CRPC), and time to second-line progression (PFS2) were compared. 2nd-line PFS defined as the time from CRPC diagnosis to progression after second-line therapy was also compared.ResultsAfter matching, a total of 170 patients were retained: 85 patients treated with docetaxel + ADT and 85 patients treated with NSAA + ADT. The median OS and CSS for docetaxel + ADT versus NSAA + ADT were not reached (NR) vs. 49 months (p = 0.02) and NR vs. 55 months (p = 0.02), respectively. Median time to CRPC and PFS2 in patients treated with docetaxel + ADT was significantly longer compared to those treated with NSAA (22 vs. 12 months; p = 0.003 and, NR vs. 28 months; p < 0.001, respectively). There was no significant difference in 2nd-line PFS between the two groups.ConclusionsOur analysis suggested that ADT with docetaxel significantly prolonged OS and CSS owing to a better time to CRPC and PFS2 in comparison to NSAA + ADT in high-volume mHSPC.

Metabolic syndrome and its pharmacologic treatment are associated with the time to castration-resistant prostate cancer.

Metabolic syndrome and its pharmacologic treatment can potentially influence the progression of prostate cancer in men receiving androgen deprivation therapy (ADT). We aimed to evaluate the association between metabolic syndrome and its pharmacologic treatment with time to castration-resistant prostate cancer (CRPC). We identified 409 men with metastatic castration-sensitive prostate cancer receiving first line ADT from 1996 to 2014 at our institution. Information concerning metabolic syndrome, statin use, aspirin use, and metformin use at initiation of ADT was collected from medical records. Time to CRPC was defined as the duration between initiating ADT and diagnosis of CRPC based on the Prostate Cancer Working Group 3 definition. Flexible parametric survival models were used to calculate hazard ratios (HR, and 95% confidence intervals, CI) of the association between metabolic conditions and time from ADT initiation to CRPC. During a median follow-up of 59 months, 87% (N = 356) men progressed to CRPC. Median time to CRPC was 19 months. Fifty-six percent of men met the definition of metabolic syndrome. Controlling for demographic and prostate cancer-specific variables, metabolic syndrome was associated with shorter time to CRPC (HR 1.41, 95% CI 1.09-1.81). Importantly, in men with metabolic syndrome, statin use was associated with a slower progression to CRPC (HR 0.70, 95% CI 0.49-0.98). Our study suggests that metabolic syndrome is a risk factor for earlier progression from castration-sensitive to castration-resistant prostate cancer and raises the possibility that treatment, such as statin use, may slow the time to progression.

OVERALL SURVIVAL EVALUATION OF PROSTATE CANCER PATIENTS TREATED WITH ANDROGEN DEPRIVATION THERAPY BY ESTIMATING FLUCTUANT PATTERNS OF METABOLIC FACTOR SERUM LEVELS

(Background) The effects of fluctuant patterns of serum alkaline phosphatase (ALP) and lactic acid dehydrogenase (LDH) levels on overall survival of patients with prostate cancer (PC) treated with androgen deprivation therapy (ADT) remain unclear. (Methods) We enrolled 236 patients with PC and divided into 3 cohorts by fluctuant patterns of serum levels of ALP and LDH between at baseline and at 1 year later, or at diagnosis of castration-resistant prostate cancer (CRPC): intermediate, within interquartile range (IQR) [I]; lower than IQR [L]; higher than IQR [H]. (Results) In the 1 year later ALP cohort, all parameters except age were significantly different. In the L cohort, 75% of patients had bone metastasis and > 50% developed CRPC or died. In the 1 year later LDH cohort, Eastern Cooperative Oncology Group-performance status (ECOG-PS) and clinical metastasis classification were significantly different among the cohorts. In the CRPC/ALP cohorts, baseline prostate-specific antigen values and clinical metastasis classification were significantly different among the cohorts, and all cases had metastasis in the L cohort. In the CRPC/LDH cohort, the L cohort had higher ECOG-PS and shorter time to CRPC. In the 1 year later ALP cohort, the hazard ratio (HR) for death of the L and H cohort to the I cohort was 3.77 and 2.27, respectively and both were significant. In the CRPC/LDH cohort, the HR for death of L cohort to I cohort was 1.99. (Conclusions) Larger fluctuations in serum ALP and LDH levels were a sign of poorer prognosis, especially for patients in the L cohort.

Tumor microenvironment pH-responsive pentagonal gold prism-based nanoplatform for multimodal imaging and combined therapy of castration-resistant prostate cancer

Given that there is lack of effective therapies for castration-resistant prostate cancer (CRPC), the combination of photothermal (PTT), photodynamic (PDT), and chemical therapy (CT) has emerged as a prominent strategy. Tumor-targeted delivery and controlled release of antitumor drug are key-elements of any combined therapy. Considering these important elements, we designed and constructed tumor microenvironment (TME)-activated nanoprobes (PGP/CaCO3@IR820/DTX-HA). The CaCO3 shell could efficiently entrap the photosensitizer IR820 and the chemotherapeutic docetaxel (DTX) on the surface of pentagonal gold prisms (PGPs) to prevent elimination from the circulation, and it could act as a TME-trigger to achieve TME-responsive drug release. After modification with hyaluronic acid, PGP/CaCO3@IR820/DTX-HA was capable of synergistic TME-triggered PTT/PDT/CT and tumor-targeted delivery. Our in vitro and in vivo studies demonstrate that PGP/CaCO3@IR820/DTX-HA could achieve synergistic antitumor effects following near-infrared (NIR)-light irradiation. In addition, using the NIR fluorescence signal from IR820 and the photoacoustic (PA) signal from PGPs, i.e., through multimodal fluorescence/photoacoustic imaging, we could monitor the in vivo distribution and excretion of PGP/CaCO3@IR820/DTX-HA. Therefore, it can be concluded that PGP/CaCO3@IR820/DTX-HA shows promising clinical translational potential as a treatment for CRPC. Statement of significanceUtilizing pentagonal gold prisms (PGPs), we constructed a multifunctional nanoplatform (PGP/CaCO3@IR820/DTX-HA) for effectively delivering agents into the tumor microenvironment (TME) for the diagnosis and therapy of castration-resistant prostate cancer (CRPC). The synthetic nanoplatform can satisfy TME-activated synergistic photothermal therapy (PTT)/photodynamic therapy (PDT)/chemical therapy (CT) and NIR fluorescence imaging/photoacoustic (PA) imaging. Hyaluronic acid (HA) on the surface of nanoplatform allowed the specific tumor-targeting capacity and biocompatibility. In conclusion, PGP/CaCO3@IR820/DTX-HA could be a promising integrated nanoplatform for CRPC diagnosis and treatment.

Development of castration resistance in prostate cancer patients treated with luteinizing hormone-releasing hormone analogues (LHRHa): results of the ANARESISTANCE study.

PurposeEvaluate the percentage of patients with prostate cancer treated with luteinizing hormone-releasing hormone analogues (LHRHa) that develop castration resistance after a follow-up period of 3 years. The secondary objective is to evaluate the variables potentially related to the progression to castration resistant prostate cancer (CRPC).MethodsA post-authorization, nation-wide, multicenter, prospective, observational, and longitudinal study that included 416 patients treated with LHRHa between 2012 and 2017 is presented. Patients were followed for 3 years or until development of CRPC, thus completing a per-protocol population of 350 patients. A Cox regression analysis was carried out to evaluate factors involved in progression to CRPC.ResultsAfter 3 years of treatment with LHRHa 18.2% of patients developed CRPC. In contrast, in the subgroup analysis, 39.6% of the metastatic patients developed CRPC, compared with 8.8% of the non-metastatic patients. The patients with the highest risk of developing CRPC were those with a nadir prostate-specific antigen (PSA) > 2 ng/ml (HR 21.6; 95% CI 11.7–39.8; p < 0.001) and those receiving concomitant medication, most commonly bicalutamide (HR 1.8; 95% CI 1–3.1, p = 0.0431).ConclusionsThe proportion of metastatic patients developing CRPC after 3 years of treatment with LHRHa is consistent with what has been previously described in the literature. In addition, this study provides new findings on CRPC in non-metastatic patients. Concomitant medication and nadir PSA are statistically significant predictive factors for the time to diagnosis of CRPC, the nadir PSA being the strongest predictor.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00345-022-04108-x.

A drug comorbidity index to predict mortality in men with castration resistant prostate cancer.

BackgroundThe Charlson Comorbidity Index is a poor predictor of mortality in men with castration resistant prostate cancer (CRPC). To improve this prediction, we created a comorbidity index based on filled prescriptions intended to be used in registry-based studies.Materials and methodsIn a population-based cohort of men with CPRC a drug comorbidity index (DCI-CRPC) was calculated based on prescriptions filled during a 365-day period before the date of CRPC diagnosis to predict mortality. Five risk categories for men with CRPC were defined based on PSA kinetics. Mortality rates were described by Kaplan-Meier curves. The predictive ability of the DCI-CRPC was compared in univariable models to that of the original DCI, derived from men in the general population, and to that of the Charlson Comorbidity Index.ResultsIn 1,885 men with CRPC the median overall survival ranged from 3.0 years (95% confidence interval [CI] 2.8 to 3.4) in the first tertile of the DCI-CRPC, to 1.0 year (95% CI 0.9 to 1.1) in the third tertile of the DCI-CRPC. The index had higher discriminative ability (C-index 0.667) than the Charlson Comorbidity Index (C-index 0.508). The discriminative ability of the DCI-CRPC was highest in the subgroup with least aggressive cancer (C-index 0.651) and lowest in men with most aggressive cancer (C-index 0.618). The performance of the DCI-CRPC was comparable to that of the original DCI.ConclusionOur newly created comorbidity index using filled prescriptions predicted death in men with CRPC better than the Charlson Comorbidity Index.

Real world treatment utilization patterns in patients with castration-resistant prostate cancer

Background Studies describing treatment utilization for castration-resistant prostate cancer (CRPC) are limited. We aimed to describe the treatment utilization of a contemporary population-based CRPC cohort between 2006 and 2016. Methods We identified 1699 men with a PC diagnosis between 2005 and 2015, who developed CRPC between 2006 and 2015 in the Stockholm region of Sweden. Demographic information, stage and grade at PC diagnosis, stage at CRPC, prostate-specific antigen (PSA) nadir, PSA doubling time, treatment utilization rate within 1 year of CRPC diagnosis, reason for stopping therapy, treatment sequence trajectory, overall and PC specific survival was described. Results Treatment for men with de novo metastatic disease (n = 463) was 32%, treatment for men with progressive metastatic disease after PC diagnosis (n = 66) was 44%, treatment for men with nonmetastatic CRPC (n = 113) was 34% and treatment for those with an unknown stage at time of CRPC diagnosis (n = 857) was 12%. Docetaxel was used in 39%, abiraterone acetate plus prednisone in 15%, enzalutamide in 13%, cabazitaxel in 11% and radium-223 in 5% of treatments. Treatment increased from 22% in 2006–2009 for metastatic cancer to 50% in 2013–2015 (p < .001). Factors associated with treatment were an unknown stage at diagnosis (OR: 0.3, 95% CI: 0.2–0.4), age ≥75 years (OR: 0.2, 95% CI: 0.1 − 0.3), PSA doubling time >3 months (OR: 0.4, 95% CI: 0.3 − 0.6) and a diagnosis between 2013 and 2015 (OR: 3.4, 95% CI: 2.0 − 5.8). Conclusions Despite treatment availability, in this large real-world cohort we found treatment utilization to remain low.