Castration-resistant Prostate Cancer Patients Research Articles

Bench to Bedside Development of [18F]Fluoromethyl-(1,2-2H4)choline ([18F]D4-FCH).

Malignant transformation is characterised by aberrant phospholipid metabolism of cancers, associated with the upregulation of choline kinase alpha (CHKα). Due to the metabolic instability of choline radiotracers and the increasing use of late-imaging protocols, we developed a more stable choline radiotracer, [18F]fluoromethyl-[1,2-2H4]choline ([18F]D4-FCH). [18F]D4-FCH has improved protection against choline oxidase, the key choline catabolic enzyme, via a 1H/2D isotope effect, together with fluorine substitution. Due to the promising mechanistic and safety profiles of [18F]D4-FCH in vitro and preclinically, the radiotracer has transitioned to clinical development. [18F]D4-FCH is a safe positron emission tomography (PET) tracer, with a favourable radiation dosimetry profile for clinical imaging. [18F]D4-FCH PET/CT in lung and prostate cancers has shown highly heterogeneous intratumoral distribution and large lesion variability. Treatment with abiraterone or enzalutamide in metastatic castrate-resistant prostate cancer patients elicited mixed responses on PET at 12-16 weeks despite predominantly stable radiological appearances. The sum of the weighted tumour-to-background ratios (TBRs-wsum) was associated with the duration of survival.

H3K27 acetylation activated-PDLIM7 promotes castration-resistant prostate cancer progression by inducing O-Glycosylation of YAP1 protein

Castration-resistant prostate cancer (CRPC) is a fatal disease that evolves from prostate cancer due to drug resistance after long-term androgen deprivation therapy. In this study, we aimed to find novel molecular targets for treating CRPC. Through peptidome, we screened out polypeptides dysregulated in the serum of CRPC patients. According to RT-qPCR analysis and cell viability detection, we chose PDZ and LIM Domain 7 (PDLIM7) as the research object. As demonstrated by loss-of-function assays, silencing of PDLIM7 could suppress CRPC cell proliferation, migration, and angiogenesis. Moreover, PDLIM7 knockdown enhanced the sensitivity of CRPC cells to docetaxel treatment. Subsequently, we found that CBP/p300 increases the H3K27ac level in the PDLIM7 promoter to activate PDLIM7. Mechanism experiments such as IP and western blot revealed that PDLIM7 interacted with YAP1 to induce O-Glycosylation of YAP1 and thus stabilize YAP1 protein. Rescue assays demonstrated that PDLIM7 promoted the malignant processes of CRPC cells through YAP1. Finally, an animal study validated that PDLIM7 aggravated tumor growth. In conclusion, our findings highlighted the oncogenic role of PDLIM7 upregulated by CBP/p300-induced H3K27ac enhancement in CRPC by stabilizing YAP1.

Abstract A007: Preclinical bone metastasis technology platform – Predictive evaluation of experimental therapies on bone metastasis

Abstract Most cancer deaths are due to metastases, and bone metastases are a considerable problem especially in breast and prostate cancer, being developed in 70-90% of advanced-stage patients. Despite major investments in oncology drug development, bone metastases are currently incurable and a high unmet medical need with only 5% of patients being alive 5 years after the diagnosis. Development of therapies for bone metastasis has been challenging due to lack of appropriate preclinical models available to support decision making in next phases of drug development. In the absence of clinically relevant preclinical bone metastasis models, the current strategy is to rely on preclinical efficacy data obtained with subcutaneous models that lack the clinically relevant local tissue microenvironment, which has a major impact on tumor growth. The use of clinically non-relevant models in preclinical-stage development may be one important reason for the current >95% failure rate of oncology drugs in clinical trials. To support predictive evaluation of therapies for bone metastatic cancers, we describe a preclinical bone metastasis technology platform for evaluating efficacy of novel therapies on bone metastases. The platform utilizes tumors growing in bone microenvironment, mimicking growth of bone metastases in patients. Syngeneic or humanized mouse models with tumor and immune cells of same species are needed for supporting development of immunotherapies, allowing interactions of tumor and immune cells in the bone metastatic microenvironment, according to the novel osteoimmuno-oncology concept. The platform provides a predictive tool for studying unique biological features associated with different types of bone metastases in cancer-type specific manner. Here we summarize case examples where results from preclinical bone metastasis studies align with clinical findings of different therapies approved or evaluated for bone metastasis. Zoledronic acid, an anti-resorptive bisphosphonate that is currently used in breast cancer patients with bone metastases to prevent cancer-induced bone loss, showed improved bone health but no effects on tumor growth. Radium-223 dichloride, an approved treatment for bone metastatic castration-resistant prostate cancer in patients, showed reduced prostate cancer growth and decreased tumor-induced bone changes. As for immunotherapies, an IDO1 inhibitor had no effects on breast cancer bone metastases and the anti-PD-1 antibody pembrolizumab had no effects on breast and prostate cancer bone metastases, predicting recent clinical findings that demonstrate lack of efficacy of anti-PD-1 in clinical prostate cancer trials. We conclude that the bone metastasis technology platform is a biologically relevant tool for preclinical evaluation of the efficacy of experimental therapies on bone metastasis, and it has been validated with positive and negative case examples, demonstrating its clinically predictive power. Citation Format: Tiina E Kähkönen, Jussi M Halleen, Jenni Bernoulli. Preclinical bone metastasis technology platform – Predictive evaluation of experimental therapies on bone metastasis [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A007.

Early response monitoring during [177Lu]Lu-PSMA I&T therapy with quantitated SPECT/CT predicts overall survival of mCRPC patients: subgroup analysis of a Swiss-wide prospective registry study

PurposeTo assess early tumor response with quantitated SPECT/CT and to correlate it with clinical outcome in metastatic castration–resistant prostate cancer (mCRPC) patients treated with 177Lutetium-PSMA I&T therapy.MethodsSingle-center, observational study, part of the prospective Swiss national cancer registry study investigating the safety and efficacy of [177Lu]Lu-PSMA I&T (EKNZ: 2021–01271) in mCRPC patients treated with at least two cycles of [177Lu]Lu-PSMA I&T 6-weekly. After the first and second cycle quantitated SPECT/CT (Symbia Intevo, Siemens) was acquired 48 h after injection (three fields of view from head to thigh, 5 s/frame) and reconstructed using xQuant® (48i, 1 s, 10-mm Gauss). Image analysis: The PSMA-positive total tumor volumes (TTV) were semi-automatically delineated using a SUV threshold of 3 with MIMencore® (version 7.1.3, Medical Image Merge Software Inc.). Changes in TTV, highest tumor SUVmax, and total tumor SUVmean between cycles 1 and 2 were calculated and grouped into a) stable or decrease and b) increase. Serum PSA levels were assessed at each therapy cycle and at follow-up until progression or death. Changes in TTV, PSA, SUVmax, and SUVmean were correlated with PSA-progression-free survival (PSA-PFS) and the overall survival (OS) using the Kaplan–Meier methodology (log-rank test).ResultsBetween 07/2020 and 04/2022, 111 patients were screened and 73 finally included in the data analysis. The median follow-up was 8.9 months (range 1.4–26.6 months). Stable or decreased TTV at cycle 2 was associated with longer OS (hazard ratio (HR) 0.28, 95% confidence interval (CI) 0.09–0.86, p < 0.01). Similar, stable, or decreased PSA was associated with longer OS (HR 0.21; CI 0.07–0.62, p < 0.01) and PSA-PFS (HR 0.34; 95% CI 0.16–0.72, p < 0.01). Combining TTV and PSA will result in an augmented prognostic value for OS (HR 0.09; CI 0.01–0.63; p < 0.01) and for PSA-PFS (HR 0.11; CI 0.02–0.68; p < 0.01). A reduction of SUVmax or SUVmean was not prognostically relevant, neither for OS (p 0.88 and 0.7) nor for PSA-PFS (p 0.73 and 0.62, respectively).ConclusionSix weeks after initiating [177Lu]Lu-PSMA I&T, TTV and serum PSA appear to be good prognosticators for OS. Combined together, TTV + PSA change demonstrates augmented prognostic value and can better predict PSA-PFS. Larger studies using TTV change prospectively as an early-response biomarker are warranted for implementing management change towards a more personalized clinical practice.

PT36 Real-World Analysis on Therapeutic Pattern and Economic Burden of Androgen-Receptor Signaling Inhibitors (ARSI) and Taxane-Based Chemotherapy Treated Metastatic Castration-Resistant Prostate Cancer Patients in Italy

PT36 Real-World Analysis on Therapeutic Pattern and Economic Burden of Androgen-Receptor Signaling Inhibitors (ARSI) and Taxane-Based Chemotherapy Treated Metastatic Castration-Resistant Prostate Cancer Patients in Italy

Negative Delta-Prostate-Specific Antigen Time Ratio as Potential New Marker of Progression-Free Survival in Castration-Resistant Prostate Cancer Patients Treated With First-Line Enzalutamide or Docetaxel

Purpose: We propose a new potential marker of progression-free survival (PFS) called negative delta-prostate-specific antigen (PSA) time ratio (NDPSATR) and compare it with conventional PSA response, defined as PSA decline ≥50% at 12 weeks from pretreatment baseline (PSAR50) in metastatic castration-resistant prostate cancer (mCRPC) patients treated with first-line enzalutamide (ENZ) or docetaxel (DTX).Materials and Methods: All patients diagnosed as mCRPC at Ajou University Hospital from 2016 were included. Delta-PSA days is PSA change between 2 consecutive measurements during a regimen multiplied by interval days. A negative delta-PSA days value represents a positive PSA response. NDPSATR is calculated by dividing the sum of days on negative delta-PSA days by total days on the regimen. Student t-test was used to compare mean values and Kaplan-Meier survival curves for PFS were obtained.Results: Of 57 patients identified, 22 and 35 were treated with ENZ and DTX, respectively. Rates of PSAR50 for ENZ and DTX were 72.7% and 20.6%, respectively. Mean NDPSATR for ENZ and DTX were 0.40 and 0.46, respectively and the difference was not statistically significant. For ENZ, median PFS (mPFS) of PSAR50 and non-PSAR50 were 14.3 and 4.8 months, respectively and there was significant difference in PFS (p=0.002). For DTX, mPFS of PSAR50 and non-PSAR50 were 15.0 and 6.5 months, respectively but there was no significant difference in PFS (p=0.055). At cutoff value of 0.4, rate of NDPSATR ≥0.4 for ENZ and DTX were 36.4% and 62.9%, respectively. For ENZ, mPFS of NDPSATR ≥0.4 and NDPSATR &lt;0.4 were not achieved and 14.1 months, respectively and there was no significant difference in PFS (p=0.895). For DTX, mPFS of NDPSATR ≥0.4 and NDPSATR &lt;0.4 were 9.7 and 6.3 months, respectively and there was a significant difference in PFS (p=0.045).Conclusions: NDPSATR ≥0.4 may be a good marker of PFS in CRPC patients treated with DTX and may replace PSAR50.

Prognostic role of neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, and pan-immune-inflammation value in metastatic castration-resistant prostate cancer patients who underwent 177Lu-PSMA-617.

This study is aimed to investigate the prognostic significance of inflammation indices, including neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and pan-immune-inflammation value (PIV) in metastatic castration-resistant prostate cancer (mCRPC) patients who had received lutetium labeled prostate-specific membrane antigen (177Lu-PSMA-617) therapy. Sixty-one mCRPC patients who received 177Lu-PSMA-617 treatment and followed up in Kocaeli University were included. The relationship between overall survival (OS) and progression-free survival (PFS) and clinical and laboratory parameters was analyzed by multivariate analyses. The mean age was 69.8 ± 6.9 years. The mean follow-up time was 53.2 ± 24 months. The median OS was 14 (95% CI: 8.8-18.1) and the median PFS was 10.4 (95% CI: 4.7-17.2) months. NLR ≥ 2.7, PLR ≥ 134.27, SII ≥ 570.39, PIV ≥ 408.59 were considered as elevated levels. In the multivariate analysis for OS, baseline ECOG performance score (HR: 1.92, 95% CI: 1.01-3.65, P = .046), high albümin (HR: 0.36, 95% CI: 0.16-0.82, P = .015), primary resistant total prostate-specific-antigen (PSA) (HR: 4.37, 95% CI: 1.84-10.35, P = .001), high NLR (HR: 3.32, 95% CI: 1.66-6.65, P = .001), high MLR (HR: 2.53, 95% CI: 1.35-4.76, P = .004), high PLR (HR: 2.47, 95% CI: 1.23-4.96, P = .01), and high SII (HR: 2.17, 95% CI: 1.09-4.32, P = .027) were associated with shorter OS. However, PIV was not associated with survival (P = .69). No factor other than the primer-resistant PSA could be identified as having an impact on PFS (for the PSA, HR: 4.52, 95% CI: 1.89-10.76, P = .001). In this study, pretreatment NLR, MLR, PLR, and SII demonstrate as powerful independent prognostic indices predicting survival in patients with mCRPC receiving 177Lu-PSMA-617 therapy.

PSMA PET/CT in Castration-Resistant Prostate Cancer: Myth or Reality?

prostate-specific membrane antigen (PSMA) ligand PET has been recently incorporated into international guidelines for several different indications in prostate cancer (PCa) patients. However, there are still some open questions regarding the role of PSMA ligand PET in castration-resistant prostate cancer (CRPC). The aim of this work is to assess the clinical value of PSMA ligand PET/CT in patients with CRPC. PSMA ligand PET has demonstrated higher detection rates in comparison to conventional imaging and allows for a significant reduction in the number of M0 CRPC patients. However, its real impact on patients' prognosis is still an open question. Moreover, in CRPC patients, PSMA ligand PET presents some sensitivity and specificity limitations. Due to its heterogeneity, CRPC may present a mosaic of neoplastic clones, some of which could be PSMA-/FDG+, or vice versa. Likewise, unspecific bone uptake (UBU) and second primary neoplasms (SNPs) overexpressing PSMA in the neoangiogenic vessels represent potential specificity issues. Integrated multi-tracer imaging (PSMA ligand and [18F]FDG PET) together with a multidisciplinary discussion could allow for reaching the most accurate evaluation of each patient from a precision medicine point of view.

Impact of germline DNA repair gene variants on prognosis and treatment of men with advanced prostate cancer

The clinical importance of germline variants in DNA repair genes (DRGs) is becoming increasingly recognized, but their impact on advanced prostate cancer prognosis remains unclear. A cohort of 221 newly diagnosed metastatic castration-resistant prostate cancer (mCRPC) patients were screened for pathogenic germline variants in 114 DRGs. The primary endpoint was progression-free survival (PFS) on first-line androgen signaling inhibitor (ARSI) treatment for mCRPC. Secondary endpoints were time to mCRPC progression on initial androgen deprivation therapy (ADT) and overall survival (OS). Twenty-seven patients (12.2%) carried a germline DRG variant. DRG carrier status was independently associated with shorter PFS on first-line ARSI [HR 1.72 (1.06–2.81), P = 0.029]. At initiation of ADT, DRG carrier status was independently associated with shorter progression time to mCRPC [HR 1.56, (1.02–2.39), P = 0.04] and shorter OS [HR 1.99, (1.12–3.52), P = 0.02]. Investigating the contributions of individual germline DRG variants on PFS and OS revealed CHEK2 variants to have little effect. Furthermore, prior taxane treatment was associated with worse PFS on first-line ARSI for DRG carriers excluding CHEK2 (P = 0.0001), but not for noncarriers. In conclusion, germline DRG carrier status holds independent prognostic value for predicting advanced prostate cancer patient outcomes and may potentially inform on optimal treatment sequencing already at the hormone-sensitive stage.

P091 - Biochemical response and overall survival rate among castrate resistant prostate cancer patients treated with docetaxel

P091 - Biochemical response and overall survival rate among castrate resistant prostate cancer patients treated with docetaxel

263MO Enzalutamide versus abiraterone plus prednisolone for Japanese non-metastatic castration-resistant prostate cancer patients: Sub-analysis from ENABLE for PCa, a multicenter, randomized controlled trial

263MO Enzalutamide versus abiraterone plus prednisolone for Japanese non-metastatic castration-resistant prostate cancer patients: Sub-analysis from ENABLE for PCa, a multicenter, randomized controlled trial

P098 - Real-world characterization of disease management and progression in metastatic and nonmetastatic castrate-resistant prostate cancer patients in Portugal: CaPA study

P098 - Real-world characterization of disease management and progression in metastatic and nonmetastatic castrate-resistant prostate cancer patients in Portugal: CaPA study

Central Nervous System-related Conditions and Associated Healthcare Resource Use Among Japanese nmCRPC Patients Based on Retrospective Claims Data.

Background: Japanese patients with prostate cancer are typically treated with primary androgen deprivation therapy (ADT), most commonly administered as a combination of a luteinizing hormone-releasing hormone (LHRH) agonist and an antiandrogen (AA). Since LHRH agonists and AA therapy can be maintained for several years, the long-term effects of these treatments on patients must be carefully considered, including the risk of concomitant central nervous system (CNS) conditions which could affect treatment choices. Objective: To describe CNS-related concomitant conditions during ADT and/or AA treatment and the subsequent healthcare resource utilization in Japanese nonmetastatic castration-resistant prostate cancer (nmCRPC) patients. Methods: Patients diagnosed with nmCRPC and CNS-related conditions while on ADT and/or AA therapy between April 2009 and August 2017 were retrospectively followed up for a maximum of 2 years using a claims database. Results: A total of 455 patients (average age, 78.5 years), were included. The 3 most common concomitant CNS-related conditions were pain (~60% of events), insomnia (~30%), and headache (2%-3%). The frequency of CNS-related conditions in these patients increased approximately threefold after starting AA therapy (before, 969 events; after, 2802). On average, a patient had 10 episodes of concomitant CNS-related conditions in a year. Medical costs did not significantly increase due to CNS-related conditions. Discussion: The most frequently reported CNS-related conditions were pain, insomnia, and headaches. Furthermore, more concomitant CNS-related conditions 1 year after CRPC diagnosis and 1 year after starting AA treatment were recorded. Conclusion: Patients with nmCRPC experience an increase in the frequency of concomitant CNS-related conditions, including pain, insomnia, and headaches, after CRPC diagnosis or starting AA treatment. Future research should explore the causes of this increased frequency.

Central Nervous System-related Conditions and Associated Healthcare Resource Use Among Japanese nmCRPC Patients Based on Retrospective Claims Data

Background: Japanese patients with prostate cancer are typically treated with primary androgen deprivation therapy (ADT), most commonly administered as a combination of a luteinizing hormone-releasing hormone (LHRH) agonist and an antiandrogen (AA). Since LHRH agonists and AA therapy can be maintained for several years, the long-term effects of these treatments on patients must be carefully considered, including the risk of concomitant central nervous system (CNS) conditions which could affect treatment choices. Objective: To describe CNS-related concomitant conditions during ADT and/or AA treatment and the subsequent healthcare resource utilization in Japanese nonmetastatic castration-resistant prostate cancer (nmCRPC) patients. Methods: Patients diagnosed with nmCRPC and CNS-related conditions while on ADT and/or AA therapy between April 2009 and August 2017 were retrospectively followed up for a maximum of 2 years using a claims database. Results: A total of 455 patients (average age, 78.5 years), were included. The 3 most common concomitant CNS-related conditions were pain (~60% of events), insomnia (~30%), and headache (2%-3%). The frequency of CNS-related conditions in these patients increased approximately threefold after starting AA therapy (before, 969 events; after, 2802). On average, a patient had 10 episodes of concomitant CNS-related conditions in a year. Medical costs did not significantly increase due to CNS-related conditions. Discussion: The most frequently reported CNS-related conditions were pain, insomnia, and headaches. Furthermore, more concomitant CNS-related conditions 1 year after CRPC diagnosis and 1 year after starting AA treatment were recorded. Conclusion: Patients with nmCRPC experience an increase in the frequency of concomitant CNS-related conditions, including pain, insomnia, and headaches, after CRPC diagnosis or starting AA treatment. Future research should explore the causes of this increased frequency.

Real life experience of compassionate use of 177Lu-PSMA-1 for metastatic castration-resistant prostate cancer patients in Leon Berard Cancer Centre

PurposeWe present a retrospective feedback of PSMA-targeted radioligands therapy (PRLT) using onsite radiolabeled 177Lu-PSMA-1 to treat metastatic castration-resistant prostate cancer patients (mCRPC) progressing after conventional treatments. MethodsOnsite radiolabeling of the PSMA-1 with 177Lu was authorized by the National Agency for the Safety of Medicines and Health Products (ANSM) after IMPD (Investigational Medicinal Product Dossier) approval allowing to treat patients before 177Lu-PSMA-617 national agreement. Patients were screened on 68Ga-PSMA and 18F-FDG PET-CTs and would be included in case of significant PSMA uptake in the majority of known lesions without mismatch between FDG and PSMA especially in liver metastases, following the THERAP trial procedure. Treatments would consist in 6 injections of 7.4GBq of 177Lu-PSMA-1 every 6 weeks following the VISION phase III trial. A clinical, biological and radiological follow-up during the treatment allowed the detection of possible adverse effects or tumor progression that should lead to treatment discontinuation, and the monitoring and characterization of the expected benefits, according to PCWG3 criteria. Whole-body SPECT-CT was performed in all patients 24hours after injection at each cycle using the VERITON® - Spectrum Dynamics to monitor lesions 177Lu-PSMA-1 uptake. ResultsBetween April 2021 and July 2022, 21 of the 24 patients screened could be included after clinical, biological and imaging screening. Ten received at least 4 injections, and 6 received all 6 injections. Three patients demonstrated a 50% reduction in PSA (PSA50), and 3 others any significant PSA evolution. The safety profile was favorable, with however grade 3 toxicities leading to permanent discontinuation of the treatment. ConclusionOn-site radiolabeled 177Lu-PSMA-1 appeared safe and lead to clinical benefit in most patients. The benefit-risk balance seems to be favorable for these multitreated mCRPC progressive patients in the absence of therapeutic alternatives. It requires a close multidisciplinary and multiprofessional collaboration within the nuclear medicine department. Further studies are necessary to specify the modalities of scans analysis, the impact of post-therapy scans, the length of the benefits observed, and the position of PRLT in the management of prostate cancers.

Comprehensive genomic profiling testing in Japanese castration-resistant prostate cancer patients: results of a single-center retrospective cohort study.

Comprehensive genomic profiling testing using a hybrid-capture next-generation sequencing is commonly used in clinical practice to employ precision medicine in cancer treatment worldwide. In this study, we aimed to analyze the profiles obtained using comprehensive genomic profiling testing that was performed in Japanese castration-resistant prostate cancer patients and to discuss the genetic findings in a real-world setting. A total of 60 cases and 57 castration-resistant prostate cancer patients underwent comprehensive genomic profiling testing between 1 January 2021 and 31 December 2022. Four types of comprehensive genomic profiling testing were selected, and clinically significant cancer-specific gene alterations were identified. The median age of patients was 74years, and the median prostate-specific antigen value at the time of submission was 18.6ng/ml. Fifty-seven (95%) of 60 cases were metastatic castration-resistant prostate cancers, and 3 cases (5%) were non-metastatic. Among all genetic alterations, androgen-receptor alteration was the most frequently detected in 17 cases (28.3%), followed by 15 cases of TP53 (25.0%), 14 cases of CDK12 (23.3%), 10 cases of phosphatase and tensin homolog (16.7%) and 9 cases of ATM (15.0%) mutations. A total of 13 patients (21.7%) received systemic therapy according to the comprehensive genomic profiling testing results. Overall, the survival rate was significantly greater in the group treated through systemic therapy based on comprehensive genomic profiling testing compared with the group without new therapeutic treatment (P=0.041). Comprehensive genomic profiling testing is recommended in castration-resistant prostate cancer patients identified as resistant to standard therapy as this can provide a new therapeutic option.

The utility of [18F]Fluciclovine PET/CT in Evaluating Nonmetastatic Castrate-Resistant Prostate Cancer Patients (nmCRPCp): diagnostic performance and impact on management.

To evaluate the role of [18F]Fluciclovine PET/CT scan in restaging nmCRPCp and its impact on management. This retrospective study included all patients with nonmetastatic castrate-resistant prostate cancer, who underwent [18F]Fluciclovine PET/CT scans for restaging who had concern for disease progression. Two radiologists independently reviewed the PET/CT studies, assigned an overall impression, and reported the site and number of radiotracer activities in consensus and impact on management was recorded. Available tissue diagnosis and/or six-month clinical and imaging follow-up were used as reference standards. Thirty-five patients were included in this study. At least one lesion was detected in 73% (26/35) of the scans. Management changed in 71% (25/35) of patients, (22 positives and three negative scans). 26.9% (7/26) of patients were found to have an oligometastatic disease. Based on the reference standards, the diagnostic performance of [18F]Fluciclovine PET/CT in detecting recurrence in nmCRCP has 86%, sensitivity, 83% specificity, 96.1% PPV, and 55.5% NPV. There was no relationship between the Gleason score and a positive PET/CT scan in our patient population. Detecting the source of recurrence is challenging in nmCRCP patients when conventional imaging fails. Given the high PPV, sensitivity, and specificity, [18F]Fluciclovine PET/CT can be used instead of conventional imaging as a first-line choice due to its superiority over bone scan and added value of detecting soft tissue metastasis regardless of the initial Gleason score. The study highlights the added value of [18F]Fluciclovine PET/CT in detecting soft tissue metastasis regardless of the initial Gleason score, which is not possible with conventional imaging such as bone scans.The study highlights the potential role of [18F]Fluciclovine PET/CT guiding management change for nonmetastatic castrate-resistant prostate cancer patients, particularly those with oligometastatic disease.

A Meta-Analysis of Randomized Clinical Trials Assessing the Efficacy of PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer.

Prostate cancer ranks as the second most common malignancy in males. Prostate cancer progressing on androgen deprivation therapy (ADT) is castration-resistant prostate cancer (CRPC). Poly-ADP ribose polymerase (PARP) inhibitors (PARPis) have been at the forefront of the treatment of CRPC. We aim to better characterize the progression-free survival (PFS) and overall survival (OS) in metastatic CRPC patients treated with PARPis. A systemic review search was conducted using National Clinical Trial (NCT), PubMed, Embase, Scopus, and Central Cochrane Registry. The improvement in overall survival was statistically significant, favoring PARPis (hazard ratio (HR) 0.855; 95% confidence interval (CI) 0.752-0.974; p = 0.018). The improvement in progression-free survival was also statistically significant, with results favoring PARPis (HR 0.626; 95%CI 0.566-0.692; p = 0.000). In a subgroup analysis, similar results were observed where the efficacy of PARPis was evaluated in a subgroup of patients without homologous recombination repair (HRR) gene mutation, which showed improvement in PFS favoring PARPis (HR 0.747; 95%CI 0.0.637-0.877; p = 0.000). Our meta-analysis of seven RCTs showed that PARPis significantly increased PFS and OS when used with or without antihormonal agents like abiraterone or enzalutamide.

Long-Term Nephrotoxicity of 177Lu-PSMA Radioligand Therapy.

β-emitting 177Lu targeting prostate-specific membrane antigen (PSMA) is an approved treatment option for metastatic castration-resistant prostate cancer. Data on its long-term nephrotoxicity are sparse. This study aimed to retrospectively evaluate post-177Lu-PSMA estimated glomerular filtration rate (eGFR) dynamics for at least 12 mo in a cohort of metastatic castration-resistant prostate cancer patients. Methods: The institutional databases of 3 German tertiary referral centers identified 106 patients who underwent at least 4 cycles of 177Lu-PSMA and had at least 12 mo of eGFR follow-up data. eGFR (by the Chronic Kidney Disease Epidemiology Collaboration formula) at 3, 6, and 12 mo after 177Lu-PSMA radioligand therapy was estimated using monoexponentially fitted curves through available eGFR data. eGFR changes were grouped (≥15%-<30%, moderate; ≥30%-<40%, severe; and ≥40%, very severe). Associations between eGFR changes (%) and nephrotoxic risk factors, prior treatment lines, and number of 177Lu-PSMA cycles were analyzed using multivariable linear regression. Results: At least moderate eGFR decreases were present in 45% (48/106) of patients; of those, nearly half (23/48) had a severe or very severe eGFR decrease. A higher number of risk factors at baseline (-4.51, P = 0.03) was associated with a greater eGFR decrease. Limitations of the study were the retrospective design, lack of a control group, and limited number of patients with a follow-up longer than 1 y. Conclusion: A considerable proportion of patients may experience moderate or severe decreases in eGFR 1 y from initiation of 177Lu-PSMA. A higher number of risk factors at baseline seems to aggravate loss of renal function. Further prospective trials are warranted to estimate the nephrotoxic potential of 177Lu-PSMA.

Untargeted lipidomics reveal association of elevated plasma C18 ceramide levels with reduced survival in metastatic castration-resistant prostate cancer patients

Emerging evidence highlights the potential prognostic relevance of circulating lipids in metastatic castration-resistant prostate cancer (mCRPC), with a proposed 3-lipid signature. This study aims to analyze the lipidomic profiles of individuals with mCRPC to identify lipid species that could serve as predictive indicators of prognosis and therapeutic response. Plasma samples were collected from mCRPC patients initiating first-line treatment (1 L) (n = 29) and those previously treated with at least two lines of therapy (> 2 L) (n = 19), including an androgen-receptor signaling inhibitor and a taxane. Employing an untargeted lipidomic approach, lipids were extracted from the plasma samples and subjected to analysis. A comprehensive identification and quantification of 789 plasma lipids was achieved. Notably, 75 species displayed significant dysregulation in > 2 L patients in comparison to the 1 L group. Among these, 63 species exhibited elevated levels, while 12 were reduced. Patients included in > 2 L cohort showed elevated levels of acylcarnitines (CAR), diacylglycerols (DG), phosphatidylethanolamines (PE), triacylglycerols (TG), and ceramides (Cer). Notably, some upregulated lipids, including CAR 14:0, CAR 24:1, Cer d18:1/16:0, Cer d18:1/18:0 (C18 Cer), Cer d18:2/18:0, Cer d18:1/24:1, and Cer d20:1/24:1, showed significant associations with overall survival (OS) in univariate models. Specifically, increased levels of C18 Cer remained significantly associated with poorer OS in the multivariate model, even after adjusting for treatment line and PSA levels (Hazard Ratio: 3.59 [95% Confidence Interval 1.51–8.52], p = 0.004). Employing quantitative mass spectrometry, our findings underscore the independent prognostic significance of C18 Cer in individuals with mCRPC. This discovery opens avenues for further studies within this field.