Biochemical Recurrence Of Prostate Cancer Research Articles

La tomographie par émission de positons aux ligands de l’antigène membranaire spécifique de la prostate (TEP-PSMA) dans le cancer de la prostate en France en 2023 : actualités et perspectives

Prostate-specific membrane antigen targeting positron emission tomography (PSMA-PET) has become since recent years increasingly important in the management of patients with prostate cancer. Initially limited to the use in patients with prostate cancer biochemical recurrence in France, PSMA-PET is now routinely use in various setting in prostate cancer patients, on the one hand for initial staging in patients with high-risk prostate cancer, and in the other hands to assess the eligibility for radioligand therapy using PSMA ligands. Other studies are currently assessing PSMA-PET in other settings such as the characterization of prostate disease, the guidance of biopsies or even as a tool for therapeutic assessment in patients with metastatic cancer. The objective of this review is to describe the current use of PSMA-PET in France in 2023, and the perspective of PSMA-PET imaging in the management of patients with prostate cancer in the future.

Modified PROMISE criteria for standardized interpretation of gastrin-releasing peptide receptor (GRPR)-targeted PET.

There are image interpretation criteria to standardize reporting prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET). As up to 10% of prostate cancer (PC) do not express PSMA, other targets such as gastrin-releasing peptide receptor (GRPR) are evaluated. Research on GRPR-targeted imaging has been slowly increasing in usage at staging and biochemical recurrence (BCR) of PC. We therefore propose a modification of the Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria (mPROMISE) for GRPR-targeted PET. [68Ga]Ga-RM2 PET data from initially prospective studies performed at our institution were retrospectively reviewed: 44 patients were imaged for staging and 100 patients for BCR PC. Two nuclear medicine physicians independently evaluated PET according to the mPROMISE criteria. A third expert reader served as standard reference. Interreader reliability was computed for GRPR expression, prostate bed (T), lymph node (N), skeleton (Mb), organ (Mc) metastases, and final judgment of the scan. The interrater reliability for GRPR PET at staging was moderate for GRPR expression (0.59; 95% confidence interval [CI] 0.40, 0.78), substantial for T-stage (0.78; 95% CI 0.63, 0.94), and almost perfect for N-stage (0.97; 95% CI 0.92, 1.00) and final judgment (0.92; 95% CI 0.82, 1.00). The interreader agreement at BCR showed substantial agreement for GRPR expression (0.70; 95% CI 0.59, 0.81) and final judgment (0.65; 95% CI 0.53, 0.78), while almost perfect agreement was seen across the major categories (T, N, Mb, Mc). Acceptable performance of the mPROMISE criteria was found for all subsets when compared to the standard reference. Interpreting GRPR-targeted PET using the mPROMISE criteria showed its reliability with substantial or almost perfect interrater agreement across all major categories. The proposed modification of the PROMISE criteria will aid clinicians in decreasing the level of uncertainty, and clinical trials to achieve uniform evaluation, reporting, and comparability of GRPR-targeted PET. Clinicaltrials.gov Identifier: NCT03113617 and NCT02624518.

Prognostic utility of RECIP 1.0 with manual and AI-based segmentations in biochemically recurrent prostate cancer from [68Ga]Ga-PSMA-11 PET images

PurposeThis study aimed to (i) validate the Response Evaluation Criteria in PSMA (RECIP 1.0) criteria in a cohort of biochemically recurrent (BCR) prostate cancer (PCa) patients and (ii) determine if this classification could be performed fully automatically using a trained artificial intelligence (AI) model.MethodsOne hundred ninety-nine patients were imaged with [68Ga]Ga-PSMA-11 PET/CT once at the time of biochemical recurrence and then a second time a median of 6.0 months later to assess disease progression. Standard-of-care treatments were administered to patients in the interim. Whole-body tumour volume was quantified semi-automatically (TTVman) in all patients and using a novel AI method (TTVAI) in a subset (n = 74, the remainder were used in the training process of the model). Patients were classified as having progressive disease (RECIP-PD), or non-progressive disease (non RECIP-PD). Association of RECIP classifications with patient overall survival (OS) was assessed using the Kaplan-Meier method with the log rank test and univariate Cox regression analysis with derivation of hazard ratios (HRs). Concordance of manual and AI response classifications was evaluated using the Cohen’s kappa statistic.ResultsTwenty-six patients (26/199 = 13.1%) presented with RECIP-PD according to semi-automated delineations, which was associated with a significantly lower survival probability (log rank p < 0.005) and higher risk of death (HR = 3.78 (1.96–7.28), p < 0.005). Twelve patients (12/74 = 16.2%) presented with RECIP-PD according to AI-based segmentations, which was also associated with a significantly lower survival (log rank p = 0.013) and higher risk of death (HR = 3.75 (1.23–11.47), p = 0.02). Overall, semi-automated and AI-based RECIP classifications were in fair agreement (Cohen’s k = 0.31).ConclusionRECIP 1.0 was demonstrated to be prognostic in a BCR PCa population and is robust to two different segmentation methods, including a novel AI-based method. RECIP 1.0 can be used to assess disease progression in PCa patients with less advanced disease.This study was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000608561) on 11 June 2015.

Diagnostic performance of 18F-labeled PSMA PET/CT in patients with biochemical recurrence of prostate cancer: a systematic review and meta-analysis.

After initial treatment of prostate cancer, increases in prostate-specific antigen (PSA) levels commonly signify potential relapse or metastasis. 18F-labeled prostate-specific membrane antigen (PSMA) is considered a promising treatment due to its favorable physical properties. To investigate the diagnostic value of 18F-PSMA PET/CT for the recurrence and/or metastasis of biochemical recurrence of prostate cancer (BRPca). A comprehensive literature search was conducted in PubMed, EMBASE, Web of Science, and the Cochrane Library databases. Combined sensitivity and specificity values for the use of 18F-PSMA PET/CT in patients with BRPca were obtained. The quality of the studies was tested using the Diagnostic Accuracy Research Quality Assessment tool. Meta-analysis was performed using STATA 15 software, and heterogeneity was subsequently tested. A total of 16 studies (1162 patients) were enrolled and had significant heterogeneity. The pooled sensitivity, specificity, and AUC values for 18F-PSMA PET/CT in the diagnosis of prostate recurrence and/or metastasis were 0.93 (0.89-0.95), 0.94 (0.85-0.98), and 0.96 (0,94-0.98), respectively. Meta-regression analyses showed that the sources of heterogeneity did not relate to ligands, study designs, or participants. The pooled sensitivity and specificity values of 18F-DCFPyL PET/CT were 0.90 (0.85-0.94) and 0.89 (0.85-0.93), respectively. The pooled sensitivity and specificity values of 18F-PSMA-1007 PET/CT were 0.89 (0.85-0.93) and 0.93 (0.70-0.99), respectively. The per-patient pooled sensitivity and specificity values were 0.92 (0.86-0.96) and 0.83 (0.41-0.97), respectively. The per-lesion pooled sensitivity and specificity values were 0.91 (0.86-0.94) and 0.91 (0.86-0.94), respectively. According to our meta-analysis, 18F-PSMA PET/CT has the potential to be critical for the diagnosis of recurrence and/or metastasis in patients with BRPca.

11C]Choline PET/CT in a Patient with Prostate Cancer Biochemical Recurrence Showing Two Suspicious Findings in the Breast and Liver.

A 79-year-old man with prostate cancer (PCa) was referred to our center to perform a [11C]Choline PET/CT for biochemical recurrence. Positron emission tomography/computed tomography (PET/CT) scan detected PCa recurrence in the prostate gland and several pelvic and abdominal lymph nodes. Two abnormal uptakes were also identified in the right breast and in the liver, respectively. Breast histological findings turned out to be gynecomastia, while the liver lesion resulted in a benign perfusion anomaly at follow-up magnetic resonance imaging (MRI). Although incidental findings were benign in this case, it is important to always investigate abnormal uptakes of [11C]Choline, as it could be an expression of further metastases or synchronous malignancies such as breast cancer and hepatocellular carcinoma.

The Diagnostic Performance of Tumor Stage on MRI for Predicting Prostate Cancer-Positive Surgical Margins: A Systematic Review and Meta-Analysis.

Surgical margin status in radical prostatectomy (RP) specimens is an established predictive indicator for determining biochemical prostate cancer recurrence and disease progression. Predicting positive surgical margins (PSMs) is of utmost importance. We sought to perform a meta-analysis evaluating the diagnostic utility of a high clinical tumor stage (≥3) on magnetic resonance imaging (MRI) for predicting PSMs. A systematic search of the PubMed, Embase databases, and Cochrane Library was performed, covering the interval from 1 January 2000 to 31 December 2022, to identify relevant studies. The Quality Assessment of Diagnostic Accuracy Studies 2 method was used to evaluate the studies' quality. A hierarchical summary receiver operating characteristic plot was created depicting sensitivity and specificity data. Analyses of subgroups and meta-regression were used to investigate heterogeneity. This meta-analysis comprised 13 studies with 3924 individuals in total. The pooled sensitivity and specificity values were 0.40 (95% CI, 0.32-0.49) and 0.75 (95% CI, 0.69-0.80), respectively, with an area under the receiver operating characteristic curve of 0.63 (95% CI, 0.59-0.67). The Higgins I2 statistics indicated moderate heterogeneity in sensitivity (I2 = 75.59%) and substantial heterogeneity in specificity (I2 = 86.77%). Area, prevalence of high Gleason scores (≥7), laparoscopic or robot-assisted techniques, field strength, functional technology, endorectal coil usage, and number of radiologists were significant factors responsible for heterogeneity (p ≤ 0.01). T stage on MRI has moderate diagnostic accuracy for predicting PSMs. When determining the treatment modality, clinicians should consider the factors contributing to heterogeneity for this purpose.

Salvage prostate bed plus elective pelvic node radiation without androgen deprivation therapy.

In men with biochemical recurrence (BCR) of prostate cancer (PCA) after radical prostatectomy (RP), there is limited data on the effectiveness of adding elective pelvic nodal radiation (EPNI) to salvage prostate bed radiation (PBRT) without androgen deprivation therapy (ADT) to prevent progression. Retrospective chart review of 326 patients treated for BCR of PCA from a single institution was performed to capture baseline pre-operative PSA, pathologic details, post-operative PSA, treatment details (radiation and ADT), subsequent failure (rising PSA), response to radiation, and subsequent outcomes after radiation. Between 2004 through 2017, 326 patients received PBRT. Majority (n = 253; 78%) did not receive ADT. Majority received EPNI (n = 227; 90%) with salvage PBRT (n = 213; 94%). The median pre-PBRT PSA was 0.50ng/ml (0.10-75.60ng/ml). Of the patients that did not receive ADT, 83% (210/253) achieved an undetectable (< 0.2ng/ml) PSA after salvage PBRT. After a median follow-up of 87months, 172 (53%) patients were without a rising PSA and 50 (15%) developed metastatic disease. Outcomes with salvage PBRT plus EPNI without ADT appear comparable to salvage PBRT plus EPNI plus ADT. These results need confirmation in a randomized setting.

Head-to-Head Comparison of [18F]F-choline and Imaging of Prostate-Specific Membrane Antigen, Using [18F]DCFPyL PET/CT, in Patients with Biochemical Recurrence of Prostate Cancer.

To analyse diagnostic and therapeutic impact of molecular imaging TNM (miTNM) stage obtained with [18F]DCFPyL versus [18F]F-choline in head-to-head comparison in biochemical recurrence (BCR) of prostate cancer (PCa). Patients with BCR of PCa after radical treatment with previous [18F]F-choline-PET/CT (negative or oligometastatic disease) were recruited to [18F]DCFPyL-PET/CT. Patients were classified according to: grade group, European Association of Urology classification, PSA, PSA doubling time (PSAdt) and PSA velocity (PSAvel). The overall detection rate (DR) and miTNM stage according to PROMISE criteria were assessed for both radiotracers and also correlated (Kappa). The influence of PSA and kinetics on both PET/CT (DR and miTNM) and predictive value of unfavourable kinetics on miTNM were determined. Cut-off PSA, PSAdt and PSAvel values able to predict PET/CT results were determined. Change in miTNM and treatment derived from [18F]DCFPyL information compared with [18F]F-choline were also evaluated. We studied 138 patients. [18F]DCFPyL showed a higher DR than [18F]F-choline (64.5% versus 33.3%) with a fair agreement. [18F]DCFPyL and [18F]F-choline detected T in 33.3% versus 19.6%, N in 27.5% versus 13.8%, and M in 30.4% versus 8.7%. Both tracers' DR showed significant associations with PSA and PSAvel. Significant association was only found between miTNM and PSA on [18F]F-choline-PET/CT (p = 0.033). For [18F]F-choline and [18F]DCFPyL-PET/CT, a PSAdt cut-off of 4.09 and 5.59 months, respectively, were able to predict M stage. [18F]DCFPyL changed therapeutic management in 40/138 patients. [18F]DCFPyL provides a higher DR and superior miTNM staging than [18F]F-choline in restaging BCR, especially with high PSA and unfavourable PSA kinetics, showing a fair agreement to [18F]F-choline.

Identification and validation of cancer-associated fibroblast-related subtypes and the prognosis model of biochemical recurrence in prostate cancer based on single-cell and bulk RNA sequencing.

Cancer-associated fibroblasts (CAFs) are an essential component of the tumor immune microenvironment that are involved in extracellular matrix (ECM) remodeling. We aim to investigate the characteristics of CAFs in prostate cancer and develop a biochemical recurrence (BCR)-related CAF signature for predicting the prognosis of PCa patients. The bulk RNA-seq and relevant clinical information were obtained from the TCGA and GEO databases, respectively. The infiltration scores of CAFs in prostate cancer patients were calculated using the MCP counter and EPIC algorithms. The single-cell RNA sequencing (scRNA-seq) was downloaded from the GEO database. Subsequently, univariate Cox regression analysis was employed to identify prognostic genes associated with CAFs. We identified two subtypes (C1 and C2) of prostate cancer that were associated with CAFs via non-negative matrix factorization (NMF) clustering. In addition, the BCR-related CAF signatures were constructed using Lasso regression analysis. Finally, a nomogram model was established based on the risk score and clinical characteristics of the patients. Initially, we found that patients with high CAF infiltration scores had shorter biochemical recurrence-free survival (BCRFS) times. Subsequently, CAFs in four pairs of tumors and paracancerous tissues were identified. We discovered 253 significantly differentially expressed genes, of which 13 had prognostic significance. Using NMF clustering, we divided PCa patients into C1 and C2 subgroups, with the C1 subgroup having a worse prognosis and substantially enriched cell cycle, homologous recombination, and mismatch repair pathways. Furthermore, a BCR-related CAFs signature was established. Multivariate COX regression analysis confirmed that the BCR-related CAFs signature was an independent prognostic factor for BCR in PCa. In addition, the nomogram was based on the clinical characteristics and risk scores of the patient and demonstrated high accuracy and reliability for predicting BCR. Lastly, our findings indicate that the risk score may be a useful tool for predicting PCa patients' sensitivity to immunotherapy and drug treatment. NMF clustering based on CAF-related genes revealed distinct TME immune characteristics between groups. The BCR-related CAF signature accurately predicted prognosis and immunotherapy response in prostate cancer patients, offering a promising new approach to cancer treatment.

Prediction of prostate cancer biochemical recurrence by using discretization supports the critical contribution of the extra-cellular matrix genes

Due to its complexity, much effort has been devoted to the development of biomarkers for prostate cancer that have acquired the utmost clinical relevance for diagnosis and grading. However, all of these advances are limited due to the relatively large percentage of biochemical recurrence (BCR) and the limited strategies for follow up. This work proposes a methodology that uses discretization to predict prostate cancer BCR while optimizing the necessary variables. We used discretization of RNA-seq data to increase the prediction of biochemical recurrence and retrieve a subset of ten genes functionally known to be related to the tissue structure. Equal width and equal frequency data discretization methods were compared to isolate the contribution of the genes and their interval of action, simultaneously. Adding a robust clinical biomarker such as prostate specific antigen (PSA) improved the prediction of BCR. Discretization allowed classifying the cancer patients with an accuracy of 82% on testing datasets, and 75% on a validation dataset when a five-bin discretization by equal width was used. After data pre-processing, feature selection and classification, our predictions had a precision of 71% (testing dataset: MSKCC and GSE54460) and 69% (Validation dataset: GSE70769) should the patients present BCR up to 24 months after their final treatment. These results emphasize the use of equal width discretization as a pre-processing step to improve classification for a limited number of genes in the signature. Functionally, many of these genes have a direct or expected role in tissue structure and extracellular matrix organization. The processing steps presented in this study are also applicable to other cancer types to increase the speed and accuracy of the models in diverse datasets.

18F]DCFPyL PET/CT versus [18F]fluoromethylcholine PET/CT in Biochemical Recurrence of Prostate Cancer (PYTHON): a prospective, open label, cross-over, comparative study.

Primary objective was to compare the per-patient detection rates (DR) of [18F]DCFPyL versus [18F]fluoromethylcholine positron emission tomography/computed tomography (PET/CT), in patients with first prostate cancer (PCa) biochemical recurrence (BCR). Secondary endpoints included safety and impact on patient management (PM). This was a prospective, open label, cross-over, comparative study with randomized treatment administration of [18F]DCFPyL (investigational medicinal product) or [18F]fluoromethylcholine (comparator). Men with rising prostate-specific antigen (PSA) after initial curative therapy were enrolled. [18F]DCFPyL and [18F]fluoromethylcholine PET/CTs were performed within a maximum time interval of 12days. DR was defined as the percentage of positive PET/CT scans identified by 3 central imaging readers. PM was assessed by comparing the proposed pre-PET/CT treatment with the local treatment", defined after considering both PET/CTs. A total of 205 patients with first BCR after radical prostatectomy (73%; median PSA = 0.46ng/ml [CI 0.16;27.0]) or radiation therapy (27%; median PSA = 4.23ng/ml [CI 1.4;98.6]) underwent [18F]DCFPyL- and/or [18F]fluoromethylcholine -PET/CTs, between July and December 2020, at 22 European sites. 201 patients completed the study. The per-patient DR was significantly higher for [18F]DCFPyL- compared to [18F]fluoromethylcholine -PET/CTs (58% (117/201 patients) vs. 40% (81/201 patients), p < 0.0001). DR increased with higher PSA values for both tracers (PSA ≤ 0.5ng/ml: 26/74 (35%) vs. 22/74 (30%); PSA 0.5 to ≤ 1.0ng/ml: 17/31 (55%) vs. 10/31 (32%); PSA 1.01 to < 2.0ng/ml: 13/19 (68%) vs. 6/19 (32%);PSA > 2.0: 50/57 (88%) vs. 39/57 (68%) for [18F]DCFPyL- and [18F]fluoromethylcholine -PET/CT, respectively). [18F]DCFPyL PET/CT had an impact on PM in 44% (90/204) of patients versus 29% (58/202) for [18F]fluoromethylcholine. Overall, no drug-related nor serious adverse events were observed. The primary endpoint of this study was achieved, confirming a significantly higher detection rate for [18F]DCFPyL compared to [18F]fluoromethylcholine, in men with first BCR of PCa, across a wide PSA range. [18F]DCFPyL was safe and well tolerated.

Biochemical Recurrence in Prostate Cancer Is Associated with the Composition of Lactobacillus: Microbiome Analysis of Prostatic Tissue

Many human pathologies, such as malignancy, are linked with specific bacteria and changes in the constituents of the microbiome. In order to examine the association between an imbalance of bacteria and prostate carcinoma, a comparison of the microbiomes present in patients with biochemical recurrence (BCR) or NO BCR (NBCR) was performed. Additionally, 16S rRNA-based next-generation sequencing was applied to identify the bacterial profiles within these tumors in terms of the bacteria and operational genes present. The percentage average taxonomic composition between the taxa indicated no difference between BCR and NBCR. In addition, alpha and beta diversity indices presented no distinction between the cohorts in any statistical method. However, taxonomic biomarker discovery indicated a relatively higher population of Lactobacillus in the NBCR group, and this finding was supported by PCR data. Along with that, differences in the operational activity of the bacterial genes were also determined. It is proposed that the biochemical recurrence was linked to the quantity of Lactobacillus present. The aim of this study was to investigate the microbiome involved in prostate carcinoma and the potential association between them.

Prediction of Prostate Cancer Biochemical and Clinical Recurrence Is Improved by IHC-Assisted Grading Using Appl1, Sortilin and Syndecan-1.

Gleason scoring is used within a five-tier risk stratification system to guide therapeutic decisions for patients with prostate cancer. This study aimed to compare the predictive performance of routine H&E or biomarker-assisted ISUP (International Society of Urological Pathology) grade grouping for assessing the risk of biochemical recurrence (BCR) and clinical recurrence (CR) in patients with prostate cancer. This retrospective study was an assessment of 114 men with prostate cancer who provided radical prostatectomy samples to the Australian Prostate Cancer Bioresource between 2006 and 2014. The prediction of CR was the primary outcome (median time to CR 79.8 months), and BCR was assessed as a secondary outcome (median time to BCR 41.7 months). The associations of (1) H&E ISUP grade groups and (2) modified ISUP grade groups informed by the Appl1, Sortilin and Syndecan-1 immunohistochemistry (IHC) labelling were modelled with BCR and CR using Cox proportional hazard approaches. IHC-assisted grading was more predictive than H&E for BCR (C-statistic 0.63 vs. 0.59) and CR (C-statistic 0.71 vs. 0.66). On adjusted analysis, IHC-assisted ISUP grading was independently associated with both outcome measures. IHC-assisted ISUP grading using the biomarker panel was an independent predictor of individual BCR and CR. Prospective studies are needed to further validate this biomarker technology and to define BCR and CR associations in real-world cohorts.

Nomogram for predicting the biochemical recurrence of prostate cancer after neoadjuvant androgen deprivation therapy

BackgroundA predictive model for biochemical recurrence (BCR) of prostate cancer (PCa) after neoadjuvant androgen deprivation therapy (nADT) has not been established. This study was aimed at determining multiparameter variables that could be used to construct a nomogram to predict the post-nADT BCR of PCa.MethodsOverall, 43 radical prostatectomy specimens from PCa patients who had undergone nADT were collected. Multiparameter variables were analyzed by univariate and then multivariate logistic analyses to identify the independent prognostic factors for predicting BCR. The predictive model was established using Lasso regression analysis.ResultsUnivariate logistic analysis revealed six variables, pathology stage; margins; categorization as group A, B, or C; nucleolus grading; percentage of tumor involvement (PTI); and PTEN status were significantly associated with the BCR of PCa (all p < 0.05). Multivariate logistic regression analysis suggested that categorization as group C, severe nucleolus grading, PTI less than or equal to 5%, and PTEN loss were positively correlated with BCR (all p < 0.05). A nomogram comprising the four variables predicting BCR was constructed, and it exhibited good discrimination (AUC: 0.985; specificity: 86.2%; sensitivity: 100%). Calibration plots for the probability of freedom from BCR at 1 and 2 years showed a good match between the prediction by the nomogram.ConclusionsWe constructed and validated a nomogram to predict the risk of BCR in PCa patients after nADT. This nomogram is a complement to the existing risk stratification systems for PCa, which could have marked implications for clinical decision-making for PCa patients after nADT.

ProSperA: Phase I study to evaluate safety, tolerability and preliminary efficacy of a bispecific PSMAxCD3 antibody in men with biochemical recurrence of prostate cancer.

TPS5114 Background: Bispecific antibodies (bsAbs), alike CAR T cells, are not yet successful in solid tumors. Recently we developed a PSMAxCD3 bsAb termed CC-1 in an IgG-based format mediating fully target cell-restricted T cell activation and potent antitumor activity (Zekri et al, EMBO Mol Med, 2020). In prostate cancer (PC), PSMA is not only expressed on the malignant cells themselves, but also on tumor vessels. Targeting the latter improves accessibility of the tumor site for immune effector cells, a critical prerequisite for success. CC-1 is under evaluation in a First in Human trial enrolling patients with castration resistant prostate carcinoma (NCT04104607) and, in combination with checkpoint inhibition, in a phase I trial enrolling patients with squamous cell carcinoma of the lung (NCT04104607). On the basis of the meanwhile available very favorable safety and preliminary efficacy data, CC-1 is now being evaluated as first line treatment in patients with biochemical recurrence (BCR) of PC (NCT05646550), where tumor burden is low and accordingly further reduced side effects and sustained efficacy are expected. Methods: This is an ongoing open label, single center phase I clinical trial evaluating CC-1 without androgen deprivation therapy as first line treatment in men with BCR of PC. Key eligibility criteria include low risk of disease progression (PSA-Doubling time &gt; 1 year after prostatectomy or interval to BCR &gt; 18 months after radiation; ISUP grade &lt; 4; PSA ≥ 0.2 ng/ml and &lt; 5 ng/ml) and no androgen deprivation therapy except in a neoadjuvant/adjuvant setting. The clinical trial consists of (i) a dose escalation part (24-42 patients) using a 3+3 design to determine overall safety, tolerability as well as maximum tolerated dose (MTD) and (ii) a dose expansion part, in which 14 patients are treated at the MTD. CC-1 is applied twice-weekly over 21 days as three-hour infusion in up to six 28-day cycles. In the first cycle, step dosing (day 1: 10µg, day 2: 28µg, day 3 and thereafter: target dose) is performed, and 7 patient cohorts receiving dose levels from 78µg to 600µg are evaluated. Premedication includes acetaminophen, dimetindene and cortisone to minimize the risk of infusion reactions and cytokine release syndrome (CRS). The primary objectives are definition of MTD and recommended phase II dose. Assessment of safety is based on the frequency of adverse events according to CTCAE v5.0. Dose limiting toxicities are defined as ≥ 3° adverse drug reactions (e.g. CRS) with predefined exceptions (e.g. temporary laboratory abnormalities). Efficacy is determined by serial PSA-measurements (PSA-response: ≥50% decrease compared to baseline). Furthermore, percentage of patients with no clinical relapse, no salvage and no subsequent antineoplastic therapy will be assessed. Clinical trial information: NCT05646550 .

A study of prospective monitoring of patients with recurrent prostate cancer using serial PSMA imaging (18F-DCFPyL).

TPS5101 Background: 18F-DCFPyL PSMA PET imaging is now FDA approved for patients with high-risk prostate cancer and those with biochemically recurrent prostate cancer (BCR). BCR has been traditionally defined as a rising PSA after definitive surgery and/or radiation have not been curative in patients without tumor findings on a CT or Tc99 bone scan. There are an estimated 25,000-50,000 new cases of BCR in the US annually. BCR patients are usually managed conservatively, often with surveillance since there is no data demonstrating interventions improve survival. Although 18F-DCFPyL will be able to detect disease at the micrometastatic/subclinical level, there is limited prospective data on how these patients should be managed. While great enthusiasm exists to utilize radiation or ADT-based regimens extrapolated from a more advanced disease state, the natural history of subclinical disease seen on 18F-DCFPyL remains unclear (Madan RA et al. J Clin Oncol 2022). Methods: The primary objective of this study is to monitor patients with recurrent prostate cancer to learn about the natural history of 18F-DCFPyL PET positive disease in this patient population. Eligible patients include those who have had prior definitive surgery or radiation, current PSA ≥0.50 ng/mL, testosterone &gt; 100 ng/mL, no evidence of soft tissue disease on CT scan/MRI and no bone lesions on bone scan. Patients will undergo initial imaging with 18F-DCFPyL scans. Those with negative findings on the initial scan will have annual repeat 18F-DCFPyL scans. Patients with positive initial scans will be scanned every 6 months. All patients will have PSA testing every 3 months and will undergo annual CT and Tc99 bone scans. Up to 250 patients will be followed for 5 years or until off-study criteria is met (including new findings on CT/bone scans consistent with metastatic disease or continuous systemic prostate cancer therapy for more than 6 months). In addition to monitoring the imaging changes, we will evaluate patterns of progression on 18F-DCPyL scans over time, analyze PSA doubling time in context of 18F-DCFPyL changes and evaluate circulating biomarkers. ClinicalTrials.gov Identifier: NCT05588128. Clinical trial information: NCT05588128 .

Phase 2 study of olaparib (without ADT) in men with biochemically recurrent prostate cancer (BCR) after prostatectomy.

5087 Background: The natural history of BCR after prostatectomy is variable and current treatment approaches include observation, salvage radiation, or androgen deprivation therapy (ADT), although many men wish to defer such therapy. We hypothesized that olaparib, now approved for use in certain men with metastatic castration resistant prostate cancer, might be an alternative option for men with high-risk BCR. Methods: This was a single arm, phase 2 trial (NCT03047135) conducted at 4 US sites. Subjects with biochemically recurrent (M0) prostate cancer, post prostatectomy, with a PSA doubling time of ≤6 months and an absolute PSA of ≥1.0 ng/mL were eligible. Patients were NOT selected based on the presence of homologous recombination repair (HRR) mutations. 51 patients were treated with olaparib 300mg twice per day, until radiographic or symptomatic progression, PSA doubling from baseline value, or drug-related toxicity. The primary endpoint was PSA50 response (50% PSA decline from baseline). Secondary endpoint was PSA progression free survival (PFS). Patients were required to undergo tissue-based next generation sequencing on the radical prostatectomy specimen to determine the presence of mutations in HRR genes ( ATM, BARD1, BRCA1/2, BRIP1, CDK12, CHEK1/2, FANCA/E/L, PALB2, RAD51B/C/D). A prespecified endpoint was to assess PSA responses in HRR[+] and HRR[–] cohorts separately. Results: Mean age was 64 years (SD 7), and 92% (47/51) of patients were White. Mean baseline PSA doubling time was 2.9 (SD 1.5) months. 55% (28/51) of pts had Gleason 6-7, 14% (7/51) had Gleason 8, and 31% (16/51) had Gleason 9-10. 86% (44/51) of patients had previously received salvage radiation. 27 patients harbored HRR mutations, the most common of which were BRCA2 (n=11), CHEK2 (n=6), and ATM (n=6). The overall PSA50 response rate was 24% (12 of 51)(95% CI 0.13, 0.38), with no responses in the HRR[–] group and 44% (12/27) PSA50 responses in the HRR[+] group (95%CI 0.26, 0.65). All 11 of the participants with a BRCA2 mutation achieved a PSA50 response. The median PSA PFS was 22 months in the HRR[+] group and 13 months in the HRR[–] group (HR 0.71; 95% CI 0.31, 1.63). Most AEs were low grade. The most common all-grade AEs were fatigue, nausea, leukopenia, anemia, and dysgeusia. Grade-3 AEs were leukopenia (9.8%), ALT/AST increase (3.9%), and anemia (2.0%). There were no grade 4–5 AEs. Conclusions: Olaparib, in the absence of ADT, can be safely administered and demonstrated activity in men with BCR prostate cancer and HRR mutations, especially for BRCA2 mutations. Additional studies to further evaluate olaparib in these patients are indicated. Clinical trial information: NCT03047135 .

Longitudinal variability in symptom burden for patients with prostate cancer (PC).

e17019 Background: Patients with PC often live for many years and can experience burdensome symptoms associated with PC and its treatment. The longitudinal fluctuations in symptom burden for a given individual with PC, or for groups with different PC disease states, are not well-described. We assessed self-rated performance status (PS), pain interference with daily activities, bother from sexual dysfunction, depression, and anxiety symptoms longitudinally for a cohort of patients with PC. Methods: For one year, patients with PC and ≥1 Urology or Medical Oncology clinic visit in the prior 6 months were emailed surveys every 60 days containing the ECOG PS instrument (range 0-4, higher scores = worse PS), PROMIS Pain Interference Short Form 4a (normalized range 1-5, higher scores = greater pain interference), PROMIS Sexual Bother (Male) items SFBOT 204, 205, and 206 (normalized range 1-5, higher scores = greater bother), PHQ-9 depression scale (range 0-27, score ≥10 considered positive for moderate symptoms), and GAD-7 anxiety scale (range 0-21, score ≥10 considered positive for moderate symptoms). We used chart review to obtain baseline characteristics and one-way ANOVA for comparisons. Results: For 201 enrolled patients, mean (SD) number of surveys completed was 5.8 (1.8) over a mean (SD) of 10.6 (3.1) months. At baseline, 50.7% had localized PC (LPC), 18.9% biochemically recurrent PC (BCR-PC), and 30.3% metastatic PC (MPC). 40.8% of patients were on androgen deprivation therapy, which was not associated with greater sexual bother (p = 0.17). Mean (SD) values for ECOG PS, pain interference, sexual bother, the PHQ-9, and the GAD-7 are shown by PC disease state (Table). For patients who completed ≥2 surveys (N = 192), mean (SD) ranges for these scales were 0.4 (0.6), 0.8 (0.9), 1.2 (0.8), 3.7 (3.3), and 2.6 (2.6), respectively. Mean range differed by PC disease state for ECOG PS (0.31 LPC vs 0.63 BCR-PC vs 0.59 MPC, p = 0.003) and pain interference (0.63 LPC vs 1.02 BCR-PC vs 0.95 MPC, p = 0.03). For patients with ≥1 positive PHQ-9 (N = 36) or GAD-7 (N = 11) screen over ≥2 surveys, a mean (SD) of 41% (30%) and 39% (33%), respectively, of their total screens were positive. Mean (SD) ranges for these patients were 8.4 (3.6) for the PHQ-9 and 8.5 (3.4) for the GAD-7 (both p &lt; 0.001 compared with those who never screened positive). Conclusions: Patients with more advanced PC had worse PS, pain, and depression, but those with BCR-PC reported greater longitudinal fluctuations in PS and pain. Patients who screened positive for depression or anxiety only did so in ~40% of their surveys, and had greater longitudinal variability in their PHQ-9/GAD-7 scores than those who never screened positive. [Table: see text]

Prime-boost immunotherapeutic trial in men with biochemical recurrence after definitive local therapy for prostate cancer.

TPS5119 Background: VTP-850 is a heterologous prime-boost immunotherapeutic consisting of 2 nonreplicating viral-vectored components: ChAdOx1-PCAQ, based on an adenoviral vector, and MVA-PCAQ, based on a modified vaccinia virus Ankara (MVA) vector. Both components encode the same 4 prostate cancer antigens: prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), six transmembrane epithelial antigen of prostate 1 (STEAP1), and 5T4, an oncofetal antigen. Preclinical studies in inbred, outbred, and HLA-A2 transgenic mice show that VTP-850 is highly immunogenic. Immune responses were measured in splenocytes using IFN-γ ELISpot assay, multiparameter flow cytometry, and targeted in vivo killing assays. The results indicate that VTP-850 can elicit T cell responses to each of the 4 encoded antigens, with the responses to PSA of greatest magnitude in all mouse strains studied. Intravenous administration of the boost resulted in a 6-fold increase in the magnitude of antigen-specific T cells induced and increased in vivo killing relative to the intramuscular boosting route1. Methods: This is a first-in-human multicenter Phase 1/2 trial to evaluate safety, PSA response rate and duration, and immunogenicity of VTP-850 in men with biochemical recurrence of prostate cancer after definitive local therapy. Phase 1 (15-18 participants) will follow a 3+3 design to determine the recommended phase 2 regimen; dose level of both ChAdOx1-PCAQ and MVA-PCAQ, and route of administration of MVA-PCAQ (IM or IV). Phase 2 will consist of 2 stages. In Stage 1, 19 additional participants will be enrolled at the chosen Phase 2 regimen. If 4 or more of the 25 participants (including the 6 Phase 1 participants who received the same regimen) have a PSA response (defined as ≥50% reduction in serum PSA compared to baseline at any time, measured twice consecutively, at least 2 weeks apart), Stage 2 will enroll 100 additional participants. Participants will be followed for 6 months or until start of new therapy (e.g. ADT) or until development of metastatic disease. Participants who have a PSA response during the 6 months follow up will be followed for up to an additional 18 months. Patients who have undergone primary therapy for prostate cancer and have biochemical recurrence are eligible. Patients must have nonmetastatic (M0) disease; serum PSA of &gt; 0.3 ng/mL for participants with prior radical prostatectomy or serum PSA of 2 ng/mL above nadir for participants with prior external beam radiation or brachytherapy; PSA doubling time ≤12 months; and testosterone &gt; 75 ng/dL. They cannot have received ADT within 6 months prior to Day 1 and cannot have received prior chemotherapy, immunotherapy or experimental agent for prostate cancer. The trial is open in the USA, with sites in Spain and Italy planned to open later in 2023. 1. Vardeu A et al 2022. Clinical trial information: NCT05617040 .

Validation of AI-based postoperative nomograms for biochemical recurrence in prostate adenocarcinoma.

e17104 Background: After radical prostatectomy (RP), a steep increase in PSA level is an early sign of the disease progression in prostate cancer, which is known as biochemical recurrence (BCR). The risk of BCR can be evaluated based on a combination of clinicopathological factors, and the patient’s Gleason score plays a significant role. However, this scoring system may have lower consistency due to interobserver reproducibility in classifying Gleason Patterns (GP) as well as in quantifying the amount of each GP. We developed AI-based nomograms, with the aim of investigating their prognostic efficacy. Methods: In this study, digitized whole-slide images (WSIs) of H&amp;E-stained prostatectomy specimens and clinical follow-up information were obtained from two sources: Pusan National University Hospital (PNUH, n = 967, event = 342) from 2010 to 2021 with the median follow-up being 3.7 years, and The Cancer Genome Atlas (TCGA, n = 352, event = 79) from 2000 to 2013 with the median follow-up 2.6 years. We used the DeepDx Prostate - RP, an AI-based prostate cancer Gleason grading model, to compute a pixel-wise probability map of each GP in WSIs. Then, a weighted sum of the probabilities and GPs was calculated for each pixel. The proposed slide-level score (AI score) was then determined by averaging them across all pixels in WSI, resulting in a value ranging from 3 to 5. Also, patients were divided into five groups using AI score thresholds (3.1, 3.5, 3.9, and 4.1), and five binary variables (AI score group 1-5) were generated, where a value of 1 indicates a patient’s categorization into a group. To evaluate predictability we created new nomograms incorporating AI scores based on existing nomograms: MSKCC and CAPRA-S. Unlike the original nomograms, the proposed nomograms do not include the Grade Group (GG) made by pathologists. Then, we fitted a Cox regression model on one of two datasets using the original and newly formed nomograms, and validated on the other dataset reporting the concordance index (c-index). Confidence intervals for the c-index were generated via the non-parametric bootstrap resampling with 9,999 samples. Results: The table shows the prognostic performance of sets of clinicopathological factors and demonstrates that the proposed AI score improved the predictive power. The nomograms with AI score group 1-5 outperformed the original nomograms, as shown in (d). Conclusions: In conclusion, we developed the AI-based nomograms which can improve the accuracy of predicting the biochemical recurrence in prostate cancer compared to the existing nomograms. [Table: see text]