Biochemical Recurrence Of Prostate Cancer Research Articles

A bicentric retrospective study of the correlation of EAU BCR risk groups with 18F-PSMA-1007 PET/CT detection in prostate cancer biochemical recurrence

The European Association of Urology (EAU) has proposed a risk stratification for patients harboring biochemical recurrence (BCR) after radical prostatectomy: ISUP < 4 and PSA doubling time (PSAdt) > 12 months for low risk, and ISUP ≥ 4 or PSAdt ≤ 12 months for high risk. This dual-center retrospective study aims to investigate the correlation between the EAU risk stratification for BCR following radical prostatectomy and the detection rate of lesions using 18F-PSMA-1007 PET/CT. Among the 71 included patients (58 high-risk, 13 low-risk), with a median PSA level of 1.43 ng/ml, PET/CT demonstrated a significantly higher positivity in the high-risk group compared to the low-risk group (72.4% vs. 38.0%, p = 0.026). Analysis of recurrence sites revealed a similar proportion of pelvic-confined disease in both groups (24.1% vs. 23.1%, p = 0.935), but a significantly higher incidence of metastatic disease in the high-risk group (51.7% vs. 15.4%, p = 0.017), with detailed findings indicating an increased prevalence of bone metastases in the high-risk BCR group (37.8% vs. 7.7%, p = 0.048). Therefore, PSMA PET/CT offers valuable insights for treatment decisions, aligning with the evolving landscape of prostate cancer management.

Added Value of [18F]PSMA-1007 PET/CT and PET/MRI in Patients With Biochemically Recurrent Prostate Cancer: Impact on Detection Rates and Clinical Management.

Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) can change management in a large fraction of patients with biochemically recurrent prostate cancer (BCR). To investigate the added value of PET to MRI and CT for this patient group, and to explore whether the choice of the PET paired modality (PET/MRI vs. PET/CT) impacts detection rates and clinical management. Retrospective. 41 patients with BCR (median age [range]: 68 [55-78]). 3T, including T1-weighted gradient echo (GRE), T2-weighted turbo spin echo (TSE) and dynamic contrast-enhanced GRE sequences, diffusion-weighted echo-planar imaging, and a T1-weighted TSE spine sequence. In addition to MRI, [18F]PSMA-1007 PET and low-dose CT were acquired on the same day. Images were reported using a five-point Likert scale by two teams each consisting of a radiologist and a nuclear medicine physician. The radiologist performed a reading using CT and MRI data and a joint reading between radiologist and nuclear medicine physician was performed using MRI, CT, and PET from either PET/MRI or PET/CT. Findings were presented to an oncologist to create intended treatment plans. Intrareader and interreader agreement analysis was performed. McNemar test, Cohen's κ, and intraclass correlation coefficients. A P-value <0.05 was considered significant. 7 patients had positive findings on MRI and CT, 22 patients on joint reading with PET/CT, and 18 patients joint reading with PET/MRI. For overall positivity, interreader agreement was poor for MR and CT (κ = 0.36) and almost perfect with addition of PET (PET/CT κ = 0.85, PET/MRI κ = 0.85). The addition of PET from PET/CT and PET/MRI changed intended treatment in 20 and 18 patients, respectively. Between joint readings, intended treatment was different for eight patients. The addition of [18F]PSMA-1007 PET/MRI or PET/CT to MRI and CT may increase detection rates, could reduce interreader variability, and may change intended treatment in half of patients with BCR. 3 TECHNICAL EFFICACY: Stage 3.

Biodistribution and radiation dosimetry of [99mTc]Tc-N4-BTG in patients with biochemical recurrence of prostate cancer

BackgroundIn patients with prostate cancer (PCa), imaging with gastrin-releasing peptide receptor (GRPR) ligands is an alternative to PSMA-targeted tracers, particularly if PSMA expression is low or absent. [99mTc]Tc-N4-BTG is a newly developed GRPR-directed probe for conventional scintigraphy and single photon emission computed tomography (SPECT) imaging. The current study aims to investigate the safety, biodistribution and dosimetry of [99mTc]Tc-N4-BTG in patients with biochemical recurrence (BCR) of PCa.ResultsNo adverse pharmacologic effects were observed. Injection of [99mTc]Tc-N4-BTG resulted in an effective dose of 0.0027 ± 0.0002 mSv/MBq. The urinary bladder was the critical organ with the highest mean absorbed dose of 0.028 ± 0.001 mGy/MBq, followed by the pancreas with 0.0043 ± 0.0015 mGy/MBq, osteogenic cells with 0.0039 ± 0.0005 mGy/MBq, the kidneys with 0.0034 ± 0.0003 mGy/MBq, and the liver with 0.0019 ± 0.0004 mGy/MBq, respectively. No focal tracer uptake suggestive of PCa recurrence could be revealed for any of the patients.Conclusion[99mTc]Tc-N4-BTG appears to be a safe diagnostic agent. Compared to GRPR-targeted PET tracers, this 99mTc-labelled SPECT agent could contribute to a broader application and better availability of this novel approach. Further research to assess its clinical value is warranted.

Explainable and visualizable machine learning models to predict biochemical recurrence of prostate cancer.

Machine learning (ML) models presented an excellent performance in the prognosis prediction. However, the black box characteristic of ML models limited the clinical applications. Here, we aimed to establish explainable and visualizable ML models to predict biochemical recurrence (BCR) of prostate cancer (PCa). A total of 647 PCa patients were retrospectively evaluated. Clinical parameters were identified using LASSO regression. Then, cohort was split into training and validation datasets with a ratio of 0.75:0.25 andBCR-related features were included in Cox regression and five ML algorithm to construct BCR prediction models. The clinical utility of each model wasevaluated by concordance index (C-index) values and decision curve analyses (DCA). Besides, Shapley Additive Explanation (SHAP) values were used to explain the features in the models. We identified 11 BCR-related features using LASSO regression, then establishing five ML-based models, including random survival forest (RSF), survival support vector machine (SSVM), survival Tree (sTree), gradient boosting decision tree (GBDT), extreme gradient boosting (XGBoost), and a Cox regression model, C-index were 0.846 (95%CI 0.796-0.894), 0.774 (95%CI 0.712-0.834), 0.757 (95%CI 0.694-0.818), 0.820 (95%CI 0.765-0.869), 0.793 (95%CI 0.735-0.852), and 0.807 (95%CI 0.753-0.858), respectively. The DCA showed that RSF model had significant advantages over all models. In interpretability of ML models, the SHAP value demonstrated the tangible contribution of each feature in RSF model. Our score system provide reference for the identification for BCR, and the crafting of a framework for making therapeutic decisions for PCa on a personalized basis.

Whole-body tumour burden on [18F]DCFPyL PET/CT in biochemical recurrence of prostate cancer: association with tumour biology and PSA kinetics.

The objective was to assess the association between molecular imaging (mi) variables on [18F]DCFPyL-PET/CT with clinical and disease characteristics and prostate specific antigen (PSA) related variables in patients with biochemical recurrence of prostate cancer (BRPC). We analysed patients with BRPC after radical treatment. We obtained clinical and PSA variables: International Society of Urology Pathology (ISUP) grade group, European Association of Urology (EAU) risk classification, PSA (PSA≤1ng/ml, 1<PSA≤2, PSA>2), PSA doubling time (PSAdt) and PSA velocity (PSAvel). All PET/CT scans were reviewed with the assistance of automated Prostate Molecular Imaging Standardized Evaluation (aPROMISE) software and lesions' segmentation in positive scans was performed using this platform. Standardized uptake value (SUV) derived variables; tumour burden variables [whole-body tumour volume (wbTV), whole-body tumour lesion activity (wbTLA) and whole-body mi PSMA (wbPSMA)] and miTNM staging were obtained. Cut-off of PSA and kinetics able to predict PET/CT results were obtained. Associations between disease and mi variables were analysed using ANOVA, Kruskal-Wallis and Spearman's correlation tests. Multivariate analysis was also performed. Two hundred and seventy-five patients were studied. [18F]DCFPyL-PET/CT were positive in 165/275 patients. In multivariate analysis, moment of biochemical recurrence, ISUP group, PSA level and PSAvel showed significant association with the detection rate. miTNM showed significant association with PSA level (p<0.001) and kinetics (p<0.001), being higher in patients with metastatic disease. Both PSA and PSAvel showed moderate correlation with wbTV, wbTLA and wbPSMA (p<0.001). A weak correlation with SUVs was found. Mean wbTV, wbTLA and wbPSMA values were significantly higher in PSA > 2ng/ml, PSAdt ≤ 6 months and PSAvel ≥ 0.2ng/ml/month groups. Also, wbTV (p=0.039) and wbPSMA (p=0.020) were significantly higher in patients with ISUP grade group 5. PSA and PSAvel cut-offs (1.15 ng/ml and 0.065 ng/ml/month) were significantly associated with a positive PET/CT. Higher PSA values, unfavourable PSA kinetics and ISUP grade group 5 were robust predictive variables of larger tumour burden variables on [18F]DCFPyL PET/CT assessed by aPROMISE platform.

Abstract 7669: Use of computational pathology to predict biochemical recurrence in prostate cancer (Pca) (Rp) patients following radical prostatectomy: Evaluation in low decipher risk category

Abstract Background: Current tools for predicting prostate cancer biochemical recurrence (BCR) after RP often depend on parameters determined by pathologists, such as tumor grade, which is known to vary between reviewers. Genomic risk classifiers provide useful information but require substantial tissue, are costly, and are not commonly accessible in many medical centers. The study presents an artificial intelligence (AI) model for automated risk assessment of biochemical recurrence (BCR) by analyzing nuclear morphologic patterns from Pca archival H&amp;E slides. Nuclear morphometric features are essential for disease diagnosis and gaining insights into cellular functions. Specifically, we sought to evaluate whether the computational pathology approach could provide additional granular risk stratification within the low-risk group identified by Decipher. Methods: The study employed two cohorts from the University of Pennsylvania D1 and D2. D1 comprised 180 patients, while D2 comprised 175 patients, including 63 individuals from the Decipher low-risk group. None of the patients in either cohort had received any pre-operative treatments. Within the Decipher cohort, a tumor segmentation model was created using the U-net deep learning network. The HoVer-Net model was used to both segment and classify nuclei. The feature extracted included a combination of nuclear texture and quantitative measurements of the spatial arrangement of nuclei. The eleven most significant features, selected via the least absolute shrinkage and selection operator (LASSO), were utilized to build a Cox regression model for predicting the risk of BCR in D1. In D2, patients were classified as either low-risk or high-risk for BCR based on the median risk score derived from D1. Results: Patients from D1 identified as high risk by the AI model experienced shorter survival, with a median BCR time of 27 months, in contrast to 55 months for those classified as low risk. The AI model demonstrated significant prognostic value for BCR in both D1 (HR = 6.82, 95% confidence interval [CI]: 3.54-13.12, p &amp;lt; 0.0019), and D2 (HR = 2.72, 95% CI: 1.53-4.82, p &amp;lt; 0.0032). Furthermore, the model effectively stratified the Decipher low-risk group in D2 into distinct low and high-risk categories (HR = 4.52, 95% confidence interval [CI]: 1.70-12.05, p &amp;lt; 0.0085). The most prognostic features identified included five related to nuclei shape diversity (Minor Axis Length, Eccentricity, Equivalent Diameter, Solidity, and Circularity) in conjunction with nine nuclear texture features. Conclusions: The AI model's findings suggest that a digital image-based prognostic classifier for prostate cancer could serve as an alternative or complementary method to molecular-based companion risk tests. Additional, independent multi-site and prospective validation of these findings are warranted. Citation Format: Kamal Hammouda, Tilak Pathak, Tuomas Mirtti, Priti Lal, Shilpa Gupta, Anant Madabhushi. Use of computational pathology to predict biochemical recurrence in prostate cancer (Pca) (Rp) patients following radical prostatectomy: Evaluation in low decipher risk category [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7669.

Head-to-head comparison of PSMA PET/CT and mpMRI for detecting biochemical recurrence of prostate cancer: A systematic review and meta-analysis

Abstract Objectives This study aimed to evaluate the performance of prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) in comparison to multiparametric magnetic resonance imaging (mpMRI) for detecting biochemical recurrence of prostate cancer (PCa). Materials and methods We conducted a comprehensive search for articles published in PubMed, Web of Science, Embase, and the Cochrane Library, spanning the inception of the database until October 26, 2022, which included head-to-head comparisons of PSMA PET/CT and mpMRI for assessing the biochemical recurrence of PCa. Results A total of 5 studies including 228 patients were analyzed. The overall positivity rates of PSMA PET/CT and mpMRI for detecting biochemical recurrence of PCa after final treatment were 0.68 (95% confidence interval [CI], 0.52–0.89) and 0.56 (95% CI, 0.36–0.88), respectively. The positivity rates of PSMA PET/CT and mpMRI for detecting local recurrence, lymph node metastasis, and bone metastases were 0.37 (95% CI, 0.30–0.47) and 0.38 (95% CI, 0.22–0.67), 0.44 (95% CI, 0.35–0.56) and 0.25 (95% CI, 0.17–0.35), and 0.19 (95% CI, 0.11–0.31) and 0.12 (95% CI, 0.05–0.25), respectively. Compared with mpMRI, PSMA PET/CT exhibited a higher positivity rate for detecting biochemical recurrence and lymph node metastases, and no significant difference in the positivity rate of local recurrence was observed between these 2 imaging modalities. Conclusions Compared with mpMRI, PSMA PET/CT appears to have a higher positivity rate for detecting biochemical recurrence of PCa. Although both imaging methods showed similar positivity rates of detecting local recurrence, PSMA PET/CT outperformed PSMA PET/CT in detecting lymph node involvement and overall recurrence.

Pretreatment prostate-specific antigen density as a predictor of biochemical recurrence in patients with prostate cancer: a meta-analysis

BackgroundA consensus has not been reached on the value of prostate-specific antigen density (PSAD) as a predictor of biochemical recurrence of prostate cancer. This meta-analysis aimed to evaluate the association between PSAD and biochemical recurrence of prostate cancer after primary treatment.MethodsTwo authors systematically searched PubMed, Web of Science, and Embase databases (up to August September 10, 2023) to identify studies that assessed the value of pretreatment PSAD in predicting biochemical recurrence after primary treatment (radical prostatectomy or radiotherapy) of prostate cancer. A random effect model was used to pool adjusted hazard ratios (HR) with 95% confidence intervals (CI) for biochemical recurrence.ResultsNine studies with 4963 patients were eligible for the meta-analysis. The reported prevalence of biochemical recurrence ranged from 4 to 55.1%. For patients with higher PSAD compared to those with low PSAD, the pooled HR of biochemical recurrence was 1.59 (95% CI 1.21–2.10). Subgroup analysis showed that the pooled HR of biochemical recurrence was 1.80 (95% CI 1.34–2.42) for patients who received radical prostatectomy, and 0.98 (95% CI 0.66–1.45) for patients who received radiotherapy.ConclusionsElevated pretreatment PSAD may be an independent predictor for biochemical recurrence of prostate cancer after radical prostatectomy. Determining PSAD could potentially improve the prediction of biochemical recurrence in patients with prostate cancer.

Head-to-head comparison of prostate-specific membrane antigen positron emission tomography/computed tomography and multiparametric magnetic resonance imaging in the detection of biochemical recurrence of prostate cancer: a systematic review and meta-analysis

Our main goal of this meta-analytical analysis was to evaluate the diagnostic effectiveness of prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) against multiparametric magnetic resonance imaging (mpMRI) in the context of identifying biochemical recurrence in patients with prostate cancer (PCa). A thorough search covering articles published until March 2023 was carried out across major databases such as PubMed, Embase, and Web of Science. Studies examining the direct comparison of PSMA PET/CT and mpMRI in patients with PCa suffering biochemical recurrence were included in the inclusion criteria. Using the renowned Quality Assessment of Diagnostic Performance Studies-2 technique, each study's methodological rigor was assessed. We analyzed data from six eligible studies involving 290 patients in total. The combined data showed that for PSMA PET/CT and mpMRI, respectively, the pooled overall detection rates for recurrent PCa after definitive treatment were 0.69 (95% confidence interval [CI]: 0.45-0.89) and 0.70 (95% CI: 0.44-0.91). The detection rates for local recurrence were specifically 0.52 (95% CI: 0.39-0.65) and 0.62 (95% CI: 0.31-0.89), while they were 0.50 (95% CI: 0.26-0.74) and 0.32 (95% CI: 0.18-0.48) for lymph node metastasis. Notably, there was no discernible difference between the two imaging modalities in terms of the overall detection rate (P = 0.95). The detection rates for local recurrence and lymph node metastasis did not differ statistically significantly (P = 0.55, 0.23). The performance of PSMA PET/CT and mpMRI in identifying biochemical recurrence in PCa appears to be comparable. However, the meta-analysis' findings came from research with modest sample sizes. In this context, more extensive research should be conducted in the future.

68Ga-RM2 PET–MRI versus MRI alone for evaluation of patients with biochemical recurrence of prostate cancer: a single-centre, single-arm, phase 2/3 imaging trial

National Comprehensive Cancer Network guidelines include prostate-specific membrane antigen (PSMA)-targeted PET for detection of biochemical recurrence of prostate cancer. However, targeting a single tumour characteristic might not be sufficient to reflect the full extent of disease. Gastrin releasing peptide receptors (GRPR) have been shown to be overexpressed in prostate cancer. In this study, we aimed to evaluate the diagnostic performance of the GRPR-targeting radiopharmaceutical 68Ga-RM2 in patients with biochemical recurrence of prostate cancer. This single-centre, single-arm, phase 2/3 trial was done at Stanford University (USA). Adult patients (aged ≥18 years) with biochemical recurrence of prostate cancer, a Karnofsky performance status of 50 or higher, increasing prostate-specific antigen concentration 0·2 ng/mL or more after prostatectomy or 2 ng/mL or more above nadir after radiotherapy, and non-contributory conventional imaging (negative CT or MRI, and bone scan) were eligible. All participants underwent 68Ga-RM2 PET-MRI. The primary outcome was the proportion of patients with PET-positive findings on 68Ga-RM2 PET-MRI compared with MRI alone after initial therapy, at a per-patient and per-lesion level. The primary outcome would be considered met if at least 30% of patients had one or more lesions detected by 68Ga-RM2 PET-MRI and the detection by 68Ga-RM2 PET-MRI was significantly greater than for MRI. Each PET scan was interpreted by three independent masked readers using a standardised evaluation criteria. This study is registered with ClinicalTrials.gov, NCT02624518, and is complete. Between Dec 12, 2015, and July 27, 2021, 209 men were screened for eligibility, of whom 100 were included in analyses. Median follow-up was 49·3 months (IQR 36·7-59·2). The primary endpoint was met; 68Ga-RM2 PET-MRI was positive in 69 (69%) patients and MRI alone was positive in 40 (40%) patients (p<0·0001). In the per-lesion analysis 68Ga-RM2 PET-MRI showed significantly higher detection rates than MRI alone (143 vs 96 lesions; p<0·0001). No grade 1 or worse events were reported. 68Ga-RM2 PET-MRI showed better diagnostic performance than MRI alone in patients with biochemical recurrence of prostate cancer. Further prospective comparative studies with PSMA-targeted PET are needed to gain a better understanding of GRPR and PSMA expression patterns in these patients. The US Department of Defense.

Biochemically recurrent prostate cancer in the era of EMBARK and PSMA PET imaging: everything has changed, except the patients.

Patients with biochemically recurrent prostate cancer (BCR) after unsuccessful curative therapies frequently have an indolent and asymptomatic disease course for years. There are no prospective data showing that treating BCR improves overall survival despite new imaging strategies and emerging therapeutic data. Managing BCR requires a unique perspective in oncology that balances toxicities and disease kinetics. Prostate specific membrane antigen (PSMA) imaging is now widely available and can define subclinical disease in patients with BCR who otherwise have negative CT and bone scans, but limited data exists showing that treating PSMA-positive disease has long term impact. A phase 3 trial demonstrated that the androgen receptor pathway inhibitor enzalutamide either alone or with androgen deprivation therapy (ADT) was superior in delaying metastasis, relative to ADT alone. Survival benefits from this study remain unknown. BCR is a heterogeneous population where overtreatment may present greater risk to patients than a disease course that is often indolent. Management of BCR should be individualized based on disease kinetics. Given the unique biology of BCR, future therapeutic research should emphasize an approach that alters disease trajectory without accompanying side effects and should explore options beyond ADT-based strategies.

[89Zr]Zr-PSMA-617 PET/CT characterization of indeterminate [68Ga]Ga-PSMA-11 PET/CT findings in patients with biochemical recurrence of prostate cancer: lesion-based analysis

BackgroundThe state-of-the-art method for imaging men with biochemical recurrence of prostate cancer (BCR) is prostate-specific membrane antigen (PSMA)-targeted positron emission tomography/computed tomography (PET/CT) with tracers containing short-lived radionuclides, e.g., gallium-68 (68Ga; half-life: ∼67.7 min). However, such imaging not infrequently yields indeterminate findings, which remain challenging to characterize. PSMA-targeted tracers labeled with zirconium-89 (89Zr; half-life: ∼78.41 h) permit later scanning, which may help in classifying the level of suspiciousness for prostate cancer of lesions previously indeterminate on conventional PSMA-targeted PET/CT.MethodsTo assess the ability of [89Zr]Zr-PSMA-617 PET/CT to characterize such lesions, we retrospectively analyzed altogether 20 lesions that were indeterminate on prior [68Ga]Ga-PSMA-11 PET/CT, in 15 men with BCR (median prostate-specific antigen: 0.70 ng/mL). The primary endpoint was the lesions’ classifications, and secondary endpoints included [89Zr]Zr-PSMA-617 uptake (maximum standardized uptake value [SUVmax]), and lesion-to-background ratio (tumor-to-liver ratio of the SUVmax [TLR]). [89Zr]Zr-PSMA-617 scans were performed 1 h, 24 h, and 48 h post-injection of 123 ± 19 MBq of radiotracer, 35 ± 35 d post-[68Ga]Ga-PSMA-11 PET/CT.ResultsAltogether, 6/20 previously-indeterminate lesions (30%) were classified as suspicious (positive) for prostate cancer, 14/20 (70%), as non-suspicious (negative). In these two categories, [89Zr]Zr-PSMA-617 uptake and lesional contrast showed distinctly different patterns. In positive lesions, SUVmax and TLR markedly rose from 1 to 48 h, with SUVmax essentially plateauing at high levels, and TLR further steeply increasing, from 24 to 48 h. In negative lesions, uptake, when present, was very low, and decreasing, while contrast was minimal, from 1 to 48 h. No adverse events or clinically-relevant vital signs changes related to [89Zr]Zr-PSMA-617 PET/CT were noted during or ~ 4 weeks after the procedure.ConclusionsIn men with BCR, [89Zr]Zr-PSMA-617 PET/CT may help characterize as suspicious or non-suspicious for prostate cancer lesions that were previously indeterminate on [68Ga]Ga-PSMA-11 PET/CT.Trial registrationNot applicable.

How the Management of Biochemical Recurrence in Prostate Cancer Will Be Modified by the Concept of Anticipation and Incrementation of Therapy.

Biochemical recurrence (BCR) after primary treatments for prostate cancer (PC) is an extremely heterogeneous phase and at least a stratification into low- and high-risk cases for early progression in metastatic disease is necessary. At present, PSA-DT represents the best parameter to define low- and high-risk BCR PC, but real precision medicine is strongly suggested to define tailored management for patients with BCR. Before defining management, it is necessary to exclude the presence of low-volume metastasis associated with PSA progression using new-generation imaging, preferably with PSMA PET/CT. Low-risk BCR cases should be actively observed without early systemic therapies. Early treatment of low-risk BCR with continuous androgen deprivation therapy (ADT) can produce disadvantages such as the development of castration resistance before the appearance of metastases (non-metastatic castration-resistant PC). Patients with high-risk BCR benefit from early systemic therapy. Even with overall survival (OS) as the primary treatment endpoint, metastasis-free survival (MFS) should be used as a surrogate endpoint in clinical trials, especially in long survival stages of the disease. The EMBARK study has greatly influenced the management of high-risk BCR, by introducing the concept of anticipation and intensification through the use of androgen receptor signaling inhibitors (ARSIs) and ADT combination therapy. In high-risk (PSA-DT ≤ 9 months) BCR cases, the combination of enzalutamide with leuprolide significantly improves MFS when compared to leuprolide alone, maintaining an unchanged quality of life in the asymptomatic phase of the disease. The possibility of using ARSIs alone in this early disease setting is suggested by the EMBARK study (arm with enzalutamide alone) with less evidence than with the intensification of the combination therapy. Continued use versus discontinuation of enzalutamide plus leuprolide intensified therapy upon reaching undetectable PSA levels needs to be better defined with further analysis. Real-world analysis must verify the significant results obtained in the context of a phase 3 study.

Phase II trial of ArtemiCoffee for men with biochemical recurrence of prostate cancer after local therapy.

Phase II trial of ArtemiCoffee for men with biochemical recurrence of prostate cancer after local therapy.

SABRE: Assessment of safety and efficacy of 64Cu-SAR-BBN in patients with PSMA-negative biochemical recurrent prostate cancer.

TPS346 Background: Between 20-40% of patients with prostate cancer (PC) will relapse within 10 years of their primary PC treatment, as identified through rising prostate-specific antigen (PSA) levels. Early diagnosis of biochemical recurrence (BCR) with accurate staging is essential to informing optimal treatment decision-making. Approximately 20% of biochemically recurrent PC patients show low or no PSMA expression on prostate-specific membrane antigen (PSMA)-targeted PET. Consequently, these patients are unlikely to benefit from PSMA-targeted agents and represent a significant unmet need for both imaging and therapy. The Gastrin Releasing Peptide receptor (GRPr) is a transmembrane G-protein coupled receptor that is upregulated in many human cancers, including PC. 64Cu-SAR-BBN, a GRPr-targeting agent, uses a radioactive form of copper, copper-64 (64Cu), to image cancers using PET. Initial clinical data have shown that 64Cu-SAR-BBN was able to detect lesions in 32% (8/25) of patients with BCR of PC and negative/equivocal PSMA PET. Methods: SABRE is a phase II, single arm, non-randomized, open-label study of 64Cu-SAR-BBN administered to patients with BCR of PC following definitive therapy. Key eligibility criteria include confirmed adenocarcinoma of the prostate, recurrence of PC based on rising PSA after definitive therapy and negative or equivocal findings for PC on an approved PSMA PET. Approximately 50 patients will be enrolled. The objectives are to assess the safety of 64Cu-SAR-BBN (200 MBq), and its ability to detect recurrent PC when traditional PSMA PET is not informative. Patients will complete a PET/CT on the same day (1 to 4 hours) and the next day (24 ±6 hours) post-dose. We hypothesize that delayed imaging may allow the detection of additional lesions compared to the scan performed on the same day of the administration of the product. The safety endpoint includes the incidence and severity of treatment-emergent adverse events and serious adverse events following the administration of 64Cu-SAR-BBN. Efficacy endpoints include correct detection rate (participant level) and positive predictive value (at participant and region level) at each scan timepoint independently. The 64Cu-SAR-BBN PET/CT scans will be assessed centrally by 3 independent, blinded readers. Each reader will evaluate the scans for the presence of pathological 64Cu-SAR-BBN uptake in the prostate bed/gland, pelvic lymph nodes (LN), extra pelvic LN, visceral/soft tissue and bone regions. Patients will be followed for up to 180 days to verify the findings. The 64Cu-SAR-BBN PET/CT results will then be assessed against a composite Reference Standard (histopathology, conventional imaging, and/or PSA levels) determined by an independent, blinded, central expert panel. 50% recruitment was reached on July 24, 2023. Clinical trial information: NCT05407311 .

Identification and validation of an individualized metabolic prognostic signature for predicting the biochemical recurrence of prostate cancer based on the immune microenvironment

BackgroundProstate cancer (PCa) is the most prevalent genitourinary malignancy in men, with a significant proportion of patients developing biochemical recurrence (BCR) after treatment. The immune microenvironment and metabolic alterations have crucial implications for the tumorigenesis and progression of PCa. Therefore, identifying metabolic genes associated with the immune microenvironment holds promise for predicting BCR and improving PCa prognosis.MethodsIn this study, ssGSEA and hierarchical clustering analysis were first conducted to evaluate and group PCa samples, followed by the use of the ESTIMATE and CIBERSORT algorithms to characterize the immunophenotypes and tumor microenvironment. The differential metabolic genes (MTGs) between groups were utilized to develop a prognostic-related signature. The predictive performance of the signature was assessed by principal component analysis (PCA), receiver operating characteristic (ROC) curve analysis, survival analysis, and the TIDE algorithm. A miRNA-MTGs regulatory network and predictive nomogram were constructed. Moreover, the expression of prognostic MTGs in PCa was detected by RT‒qPCR.ResultsPCa samples from the TCGA cohort were separated into two groups: the immune-low group and immune-high group. Forty-eight differentially expressed MTGs between the groups were identified, including 37 up-regulated and 11 down-regulated MTGs. Subsequently, CEL, CYP3A4, and PDE6G were identified as the genes most strongly associated with the BCR of PCa patients and these genes were utilized to establish the MTGs-based prognostic signatures. PCA, ROC curves analysis, Kaplan–Meier survival analysis, and the nomogram all showed the good predictive ability of the signature regardless of clinical variables. Furthermore, the MTGs-based signature was indicated as a potential predictive biomarker for immunotherapy response. Nine miRNAs involved in the regulation of prognostic MTGs were determined. In addition to the CEL gene, the PDE6G and CYP3A4 genes were expressed at higher levels in PCa samples.ConclusionsThe MTGs-based signature represents a novel approach with promising potential for predicting BCR in PCa patients.

Updates on Management of Biochemical Recurrent Prostate Cancer.

Patients with biochemical recurrent prostate cancer (BCR) are a heterogeneous group, whereby a personalized approach to management is critical. Patients with high-risk features such as PSA doubling time (PSADT) ≤ 9-12 months warrant earlier imaging for metastasis detection and consideration for intensified therapy (beyond intermittent androgen deprivation alone) during this phase of BCR-only disease. The BCR phase represents a unique opportunity to impact disease survival and delay metastasis progression. There is compelling evidence from the EMBARK trial that ADT monotherapy is no longer the optimal consideration for high-risk BCR patients.

Diagnostic accuracy of bone scan at different PSA levels in biochemical recurrence of prostate cancer

ObjectiveTo determine the diagnostic accuracy of Bone Scan at different PSA levels for detecting skeletal metastases in men with biochemical recurrence of prostate cancer. MethodsWe conducted a retrospective review of the statewide RIS-PACS to identify 251 men with biochemical recurrence who underwent both a Bone Scan and Ga68 PSMA PET/CT (within 2 months of each other) between September 2019 and December 2022 at a single institution. The Ga68 PSMA PET/CT report was considered to be the reference standard. ResultsThe median age was 72 years (IQR 67–76) with a median PSA level of 1 ng/ml (IQR 0.25–2.8). Using Ga68 PSMA PET/CT as the reference standard, 68/251 patients (25%) were positive for osseus metastases. Overall sensitivity and specificity of Bone Scan was 51% (95% CI 40–64%) and 99% (95% CI 98–100%) respectively. Using PSA banding, a PSA threshold of 20 ng/ml provided the greatest discriminatory benefit with sensitivity of the Bone Scan below the threshold being 46% (95% CI 33–59%) and above the threshold being 89% (95% CI 68–100%). Specificity remained consistently high both below and above this threshold. ConclusionBone Scan provides greater diagnostic accuracy for detecting skeletal metastases in biochemical recurrence when the PSA level is above 20 ng/ml. This knowledge is valuable in optimising imaging algorithms in biochemical recurrence, particularly in regions where PSMA PET/CT is less readily available or affordable.

ACOX2 Serves as a Favorable Indicator Related to Lipid Metabolism and Oxidative Stress for Biochemical Recurrence in Prostate Cancer.

Given the heterogeneity of tumors, there is an urgent need for accurate prognostic parameters in prostate cancer (PCa) patients. Lipid metabolism (LM) reprogramming and oxidative stress (OS) play a vital role in the progression of PCa. In this work, we identified five LM-OS-related genes (including ACOX2, PPRAGC1A, PTGS1, PTGS2, and HAO1) associated with the biochemical recurrence (BCR) of PCa. Subsequently, a prognostic signature was established based on these five genes. Kaplan-Meier survival estimates, receiver operating characteristic curves, and relationship analysis between risk score and clinical characters were applied to measure the robustness of the signature in an external cohort. A nomogram of risk score combined with clinical characteristics was constructed for clinical application. Functional enrichment analysis suggested that the underlying mechanism related to the signature included the calcium signaling, lipid transport, and cell cycle signaling pathways. Furthermore, WEE1 inhibitor was identified as a potential agent related to the cell cycle for high-risk patients. The mRNA expression and the prognostic value of the five genes were determined, and ACOX2 was identified as the key gene related to the prognostic signature. The protein expression of ACOX2 was measured in a prostate tissue microarray through an immunohistochemistry assay, confirming the bioinformatics results. By constructing the ACOX2-overexpressing PCa cell lines PC-3 and 22Rv1, the biological function of PCa cells was investigated. The cell viability, colony formation, migration, and invasion ability of PCa cell lines overexpressing ACOX2 were hindered. Decreased cellular lipid content and elevated cellular ROS content were observed in ACOX2-overexpressing PCa cell lines with reduced G2/M phases. In conclusion, this work presents the first prognostic signature specifically focused on LM-OS for PCa. ACOX2 could serve as a favorable indicator for the BCR in PCa. Further experiments are required to identify the potential underlying mechanism.

Quantification of collagen content and stromal cellularity within reactive stroma is predictive of prostate cancer biochemical recurrence and specific death

Semiquantitative reactive stromal grading has been shown to be a predictor of biochemical recurrence and prostate cancer (PCa) specific death. It has been extensively validated. In this study we tested novel technologies to introduce quantitative measures of host response, in particular collagen content and stromal cellularity. We use 3 large retrospective cohorts, the Baylor College of Medicine cohort, the Brady cohort and the Pound cohort. Slides were stained and digitized using image deconvolution and analyzed using image segmentation and image analyses. PicroSirius red stain histochemical stains were used for collagen quantification. Area of cancer and stroma were measured independently, without regard to quality of stroma. Cellularity, in each compartment, was measured using image deconvolution, image segmentation and image analysis. Two biomarkers were tested in 3 independent cohorts with two endpoints, biochemical recurrence and prostate cancer specific death. Stromal cellularity (qCollCell) and stromal collagen area (qCollArea) are independently predictive biochemical recurrence in the Hopkins Brady cohort, particularly in Gleason 6–7 patients. Multivariate analysis demonstrated that increased stroma cellularity (qCollCell) was a significant predictor of PCa specific death, when compared to an established model of PCa, in the Baylor cohort. Stromal collagen (qCollArea) independently predicts PCa-specific death in the Hopkins Pound cohort. The introduction of a computerized quantitative test of the host response increases the probability that this test will be reproducible in other cohorts. The ability to improve prediction of prostate cancer specific death might lie in the study of the host and its response.