Search Results (887)

Background: Prostate cancer (PC) is the second leading cause of cancer-related death in men in the United States. A subset of patients develops non-metastatic, castration-resistant PC (nmCRPC), for which management requires a personalized consideration for appropriate treatment. However, there is no consensus regarding when to switch from androgen deprivation therapy (ADT) to more aggressive treatments like abiraterone or enzalutamide. Methods: We analyzed 5037 nmCRPC patients and employed a Weibull Time to Event Recurrent Neural Network to identify patients who would benefit from switching from ADT to abiraterone/enzalutamide. We evaluated this model using differential treatment benefits measured by the Kaplan–Meier estimation and milestone probabilities. Results: The model achieved an area under the curve of 0.738 (standard deviation (SD): 0.057) for patients treated with abiraterone/enzalutamide and 0.693 (SD: 0.02) for patients exclusively treated with ADT at the 2-year milestone. The model recommended 14% of ADT patients switch to abiraterone/enzalutamide. Analysis showed a statistically significant absolute improvement using model-recommended treatments in progression-free survival (PFS) of 0.24 (95% confidence interval (CI): 0.23–0.24) at the 2-year milestone (PFS rate increasing from 0.50 to 0.74) with a hazard ratio of 0.44 (95% CI: 0.39–0.50). Conclusions: Our model successfully identified nmCRPC patients who would benefit from switching to abiraterone/enzalutamide, demonstrating potential outcome improvements. Full article

Prostate cancer accounts for approximately 1.5 million new diagnoses and 400,000 deaths every year worldwide, and demographic projections indicate a near-doubling of both figures by 2040. Despite existing treatments, 10–20% of patients eventually progress to metastatic castration-resistant disease (mCRPC). The median overall survival (OS) after progression to mCPRC drops to 24 months, and efficacy drops severely after each additional line of treatment. Omics platforms have reached advanced levels and enable the acquisition of high-resolution large datasets that can provide insights into the molecular mechanisms underlying PCa pathology. Genomics, especially DDR (DNA damage response) gene alterations, detected via tissue and/or circulating tumor DNA, efficiently guides therapy in advanced prostate cancer. Given recent developments, we have performed a comprehensive literature search to cover recent research and clinical trial reports (over the last five years) that integrate omics along three converging trajectories in therapeutic development: (i) predicting response to approved agents with demonstrated survival benefits, (ii) stratifying patients to receive therapies in clinical trials, (iii) guiding drug development as part of drug repurposing frameworks. Collectively, this review is intended to serve as a comprehensive resource of recent advancements in omics-guided therapies for advanced prostate cancer, a clinical setting with existing clinical needs and poor outcomes. Full article

Bone is the most frequent site of distant metastasis in advanced prostate cancer (PCa), contributing substantially to patient morbidity and mortality. Hypoxia, a defining feature of the solid tumour microenvironment, plays a pivotal role in driving bone-tropic progression by promoting epithelial-to-mesenchymal transition (EMT), cancer stemness, extracellular matrix (ECM) remodelling, and activation of key signalling pathways such as Wingless/Integrated (Wnt) Wnt/β-catenin and PI3K/Akt. Hypoxia also enhances the secretion of extracellular vesicles (EVs), enriched with pro-metastatic cargos, and upregulates bone-homing molecules including CXCR4, integrins, and PIM kinases, fostering pre-metastatic niche formation and skeletal colonisation. In this review, we analysed current evidence on how hypoxia orchestrates PCa dissemination to bone, focusing on the molecular crosstalk between HIF signalling, Wnt activation, EV-mediated communication, and cellular plasticity. We further explore therapeutic strategies targeting hypoxia-related pathways, such as HIF inhibitors, hypoxia-activated prodrugs, and Wnt antagonists, with an emphasis on overcoming therapy resistance in castration-resistant PCa (CRPC). By examining the mechanistic underpinnings of hypoxia-driven bone metastasis, we highlight promising translational avenues for improving patient outcomes in advanced PCa. Full article

Background/Objectives: Androgen deprivation therapy (ADT) is widely used to manage prostate cancer (PC), but the emergence of treatment resistance remains a major clinical challenge. Although the GST family has been implicated in drug resistance, the specific role of GSTM5 remains poorly understood. This study investigates whether GSTM5, alone or in combination with clinical variables, can improve patient stratification based on the risk of early treatment resistance. Methods: In silico analyses were performed to examine GSTM5’s role in protein interactions, molecular pathways, and gene expression. The rs3768490 polymorphism was genotyped in 354 patients with PC, classified by ADT response. Descriptive analysis and logistic regression models were applied to evaluate associations between genotype, clinical variables, and ADT response. GSTM5 expression related to the rs3768490 genotype and ADT response was also analyzed in 129 prostate tissue samples. Results: The T/T genotype of rs3768490 was significantly associated with a lower likelihood of early ADT resistance in both individual (p = 0.0359, Odd Ratios (OR) = 0.18) and recessive models (p = 0.0491, OR = 0.21). High-risk classification according to D’Amico was strongly associated with early progression (p < 0.0004; OR > 5.4). Combining genotype and clinical risk improved predictive performance, highlighting their complementary value in stratifying patients by treatment response. Additionally, GSTM5 expression was slightly higher in T/T carriers, suggesting a potential protective role against ADT resistance. Conclusions: The T/T genotype of rs3768490 may protect against ADT resistance by modulating GSTM5 expression in PC. These preliminary findings highlight the potential of integrating genetic biomarkers into clinical models for personalized treatment strategies, although further studies are needed to validate these observations. Full article

Prostate cancer continues to be the most common cause of cancer-related disease and mortality among men worldwide, especially in the advanced stages, notably metastatic castration-resistant prostate cancer (mCRPC), which poses significant treatment challenges. Docetaxel, a widely used chemotherapeutic agent, has long served as the standard treatment, offering survival benefits and mitigation. However, its clinical impact is frequently undermined by the development of chemoresistance, which is a formidable challenge that leads to treatment failure and disease progression. The mechanisms driving docetaxel resistance are diverse and complex, encompassing modifications in androgen receptor signaling, drug efflux transporters, epithelial-mesenchymal transition (EMT), microtubule alterations, apoptotic pathway deregulation, and tumor microenvironmental influences. Recent evidence suggests that extracellular RNAs influence drug responses, further complicating the resistance landscape. This review offers a broad discussion on the mechanisms of resistance and explores novel therapeutic approaches to address them. These include next-generation taxanes, targeted molecular inhibitors, immunotherapies, and combination regimens that can be designed to counteract specific resistance pathways. By broadening our understanding of docetaxel resistance, this review highlights potential strategies to improve therapeutic efficacy and the potential to enhance outcomes in patients with advanced treatment-resistant prostate cancer. Full article

Background: Second-generation androgen receptor signaling inhibitors are one of the main treatment options in metastatic castration-resistant prostate cancer (mCRPC). Nonetheless, a considerable proportion show limited response to treatment, which indicates the need for convenient, easily accessible predictor biomarkers, a role suited for liquid biopsy. Methods: We conducted a PRISMA-compliant systematic review of four databases (Embase, Medline, Scopus, Web of Science) to identify all studies (observational studies and clinical trials) investigating cell-free DNA, circulating tumor cells, exosomes, and circulating RNAs as prognostic markers in metastatic castration-resistant patients starting androgen receptor signaling inhibitors. We excluded studies that evaluated combination therapies, rare histological subtypes or included nonmetastatic or castrate-sensitive disease. We also evaluated whether published papers followed reporting guidelines (REMARK, STROBE, or CONSORT for abstracts). Results: We identified a total of 123 reports, from which we identified only a few well-studied and consistent biomarkers: androgen receptor overexpression/copy number gain and splice variant 7, as well as disease burden markers (circulating tumor DNA fraction and circulating tumor cell concentration). Alterations or copy number loss in tumor suppressors PTEN, RB1, and TP53 were second in terms of quantity and consistency of evidence. However, a large majority of identified biomarkers were relatively understudied or inconsistent. We identified two potential vulnerabilities: inconsistent adherence to reporting guidelines and the under-inclusion of patients of non-Western European ancestry. Conclusions: A large number of biomarkers were linked to worse outcomes in prostate cancer; nonetheless, in most cases, the evidence is limited or inconsistent, or even contradictory. The main exceptions pertain to androgen receptor signaling and disease burden, and, to a smaller extent, to certain tumor suppressor genes. Further studies are needed to confirm their clinical utility, using clear and consistent methodologies and including patients from currently understudied populations. Full article

Positron emission tomography (PET) and liquid biopsy have independently transformed prostate cancer management. This review explores the complementary roles of PET imaging and liquid biopsy in prostate cancer, focusing on their combined diagnostic, monitoring, and prognostic potential. A systematic search of PubMed, Scopus, and Cochrane Library databases was conducted to identify human studies published in English up to January 2025. Seventeen studies met the inclusion criteria and were analyzed according to PRISMA guidelines. Across the included studies, PET-derived imaging metrics, such as metabolic activity and radiotracer uptake, correlated consistently with liquid biopsy biomarkers, including circulating tumor cells and cell-free DNA. Their joint application demonstrated added value in early detection, treatment monitoring, and outcome prediction, particularly in castration-resistant prostate cancer. Independent and synergistic prognostic value was noted for both modalities, including survival outcomes such as overall survival and progression-free survival. Combining PET imaging and liquid biopsy emerges as a promising, non-invasive strategy for improving prostate cancer diagnosis, monitoring, and therapeutic stratification. While preliminary findings are encouraging, large-scale prospective studies are essential to validate their integrated clinical utility. Full article

Background: This Phase 2 trial evaluated the efficacy, tolerability, and safety of [¹⁷⁷Lu]Lu-PSMA-617 (¹⁷⁷Lu-PSMA-617) in patients with ≥1 measurable lesion and progressive prostate-specific membrane antigen-positive (PSMA+) metastatic castration-resistant prostate cancer (mCRPC) in Japan. Methods: This study comprises four parts; data from three parts are presented here. Part 1 evaluated safety and tolerability; Parts 2 (post-taxane) and 3 (pre-taxane/taxane-naive) assessed the overall response rate (ORR; primary endpoint), overall survival (OS), radiographic progression-free survival (rPFS), disease control rate (DCR), PFS, and safety; and Part 4 is the expansion part. Patients received 7.4 GBq (±10%) ¹⁷⁷Lu-PSMA-617 Q6W for up to six cycles. Results: Of the 35 patients who underwent a [⁶⁸Ga]Ga-PSMA-11 (⁶⁸Ga-PSMA-11) PET/CT scan, 30 received ¹⁷⁷Lu-PSMA-617 (post-taxane, n = 12; pre-taxane, n = 18). No dose-limiting toxicity was noted in Part 1 (n = 3). Post- and pre-taxane patients had a median of three and five cycles, respectively. The primary endpoint, ORR, met the pre-specified threshold, with the lower limit of the 90% confidence interval (CI) above the threshold of 5% for post-taxane and 12% for pre-taxane. Post- and pre-taxane patients had an ORR of 25.0% (90% CI: 7.2–52.7) and 33.3% (90% CI: 15.6–55.4), respectively. In post- and pre-taxane patients, the DCR was 91.7% and 83.3%, the median rPFS was 3.71 and 12.25 months, and the median PFS was 3.71 and 5.59 months, respectively. The median OS was 14.42 and 12.94 months in post- and pre-taxane patients, respectively. The most common adverse events were constipation, decreased appetite, decreased platelet count, anemia, and nausea. Conclusions: The primary endpoint (ORR) was met. The safety profile of ¹⁷⁷Lu-PSMA-617 was consistent with the VISION and PSMAfore studies, with no new safety signals in the Japanese patients with mCRPC. Full article

Prostate cancer, a malignancy of significant prevalence, affects approximately half a million men in Europe, with one in twelve males receiving a diagnosis before reaching the age of 75. Radiotheranostics represents a paradigm shift in prostate cancer treatment, leveraging radionuclides for diagnostic and therapeutic applications, with PSMA emerging as the primary molecular target. Regulatory bodies have approved various PSMA-targeted radiodiagnostic agents, such as [¹⁸F]DCFPyL (PYLARIFY^®, Lantheus Holdings), [¹⁸F]rhPSMA-7.3 (POSLUMA^®, Blue Earth Diagnostics), and [⁶⁸Ga]Ga-PSMA-11 (LOCAMETZ^®, Novartis/ILLUCCIX^®, Telix Pharmaceuticals), as well as therapeutic agents like [¹⁷⁷Lu]Lu-PSMA-617 (PLUVICTO^®, 15 Novartis). The approval of PLUVICTO^® in March 2022 for patients with metastatic castration-resistant prostate cancer who have undergone prior treatments, including androgen receptor pathway-targeting agents and taxane-based chemotherapy, represents a significant advancement. Other radionuclides like ¹⁶¹Tb, ¹⁴⁹Tb, ²²⁵Ac, ²²⁷Th, ²²³Ra, ²¹¹At, ²¹³ Bi, ²¹²Pb, ⁸⁹Zr, and ¹²⁵I are presented, emphasizing their clinical implementation or the stage of clinical trial they are in in the flow to biomedical implementation. Three clinically wise used radionuclides ¹⁷⁷Lu, ²²⁵Ac, ²²³Ra are shown along with their characteristics. This review aims to elucidate the molecular mechanisms underpinning PSMA, explore the clinical applications of PSMA-targeted radiotheranostics, and critically examine the diverse challenges these therapies encounter in the treatment of prostate cancer. Full article

Background: Treatment of metastatic cancer remains a challenge, because cancer cells acquire resistance even to the most contemporary therapies. This study analyzed the role of the phosphoprotein Stathmin 1 (STMN1) in regulating cancer cell growth and metastatic potential. Methods: Public datasets with metastatic castration-resistant prostate cancer (mCRPC) and breast cancer (BC) were analyzed to determine the interrelationship between STMN1, hepatocyte growth factor (HGF) and MET proto-oncogene (MET) expression, overall survival, and response to chemotherapy. Site-directed mutagenesis, cell cycle analysis, proliferation, and migration and invasion assays determined the impact of STMN1 phosphorylation on proliferation and metastatic potential. Results: Increased STMN1 associates with HGF and MET gene expression in mCRPC, and taxane chemotherapy further increases HGF expression. STMN1 and HGF are highest, and overall survival is poorest in mCRPC in the liver compared to other sites, implying the metastatic site influences their expression levels and potentially the pattern of metastatic spread. Increased STMN1 and MET also predict taxane responsiveness in BC patients. Analysis of STMN1 serine (S)16, 25, 38, and 63 determined that total (t) STMN1 and STMN1 S16 phosphorylation (pSTMN1^S16) are co-regulated by HGF/MET during cell cycle progression, pSTMN1^S16 alone can promote cell proliferation, and pSTMN1^S16 shortens the cell cycle similar to HGF treatment, while STMN1^S16 dephosphorylation lengthens the cell cycle to arrest cell growth in G2/M, similar to HGF plus the MET inhibitor AMG337. Importantly, STMN1^S16 does not promote metastasis. Conclusions: Selectively inhibiting STMN1^S16 phosphorylation may provide an alternative strategy for inhibiting MET-mediated cell growth to eliminate metastatic cancer cells and inhibit further metastasis. Full article

Background/Objectives: Red bone marrow irradiation is a major concern for patients with advanced prostate cancer undergoing [¹⁷⁷Lu]Lu-PSMA therapy. However, low uptake in the red bone marrow and the presence of bone lesions complicate image-based red bone marrow dosimetry. This study aimed to investigate the general feasibility of image-based red bone marrow activity estimation for [¹⁷⁷Lu]Lu-PSMA treatment and to develop a fully automated workflow for clinical implementation. Methods: In the first part of the study, 175 virtual patient phantoms with realistic ¹⁷⁷Lu activity distributions were generated based on 639 pre-therapeutic [¹⁸F]F-PSMA-1007 PET/CT scans. The SIMIND Monte Carlo tool was used to simulate the ¹⁷⁷Lu SPECT acquisitions (24 h post-injection (p.i.)), which were used to assess the uncertainty of red bone marrow activity estimation. In the second part, red bone marrow self- and cross-absorbed doses were estimated for four therapy cycles of 20 patients. Results: The simulation study shows a significant overestimation of activity in skeletal sites with bone lesions, with median recovery coefficients (RCs) across all phantoms yielding a median of 225% (range: 106–1015%). In contrast, the median RCs were markedly lower in skeletal sites neighboring or distant to lesion-carrying sites (105% [72–163%] and 107% [77–130%], respectively). The median total absorbed dose to the red bone marrow was 20.8 mGy/GBq (range: 5.6–297.9 mGy/GBq). Median blood levels decreased with an increasing median cumulative total absorbed dose. Conclusions: Reliable estimation of activity concentration in skeletal sites without bone lesion infiltration has been shown to be feasible. Based on this finding, an automated workflow for routine image-based red bone marrow dosimetry was developed. Full article

PARP inhibitors (PARPi), alone or in combination with androgen receptor signaling inhibitors (ARSi), have shown clinical benefit in metastatic castration-resistant prostate cancer (mCRPC), particularly in tumors with homologous recombination repair (HRR) gene alterations. Recent data from the TALAPRO-2 trial complete the current evidence on PARPi–ARSi combination strategies in this setting. Background/Objectives: To evaluate the efficacy and safety of PARPi-based therapies—monotherapy and combination with ARSi—in patients with mCRPC, focusing on molecular subgroups defined by DNA repair alterations. Methods: We conducted a systematic review and meta-analysis of phase III randomized controlled trials (RCTs) assessing PARPi as monotherapy or in combination with ARSi. Searches were performed in PubMed, EMBASE, the Cochrane Library, and oncology conference proceedings up to February 2025. Outcomes included radiographic progression-free survival (rPFS), overall survival (OS), second progression-free survival (PFS2), and grade ≥3 adverse events (AEs). Data were pooled using a random-effects model, with subgroup analyses by DNA repair status. Results: Five RCTs (n = 2921) were I confirmincluded: three on combination therapy (n = 2271) and two on monotherapy (n = 650). Combination therapy improved rPFS in the ITT (HR = 0.64; 95% CI: 0.56–0.74), HRRm (HR = 0.55; 95% CI: 0.44–0.68), and BRCAm (HR = 0.33; 95% CI: 0.18–0.58) subgroups. OS was also improved in the ITT (HR = 0.80; 95% CI: 0.70–0.92), HRRm (HR = 0.68; 95% CI: 0.55–0.83), and BRCAm (HR = 0.54; 95% CI: 0.34–0.85) groups. No benefit was observed in non-HRRm patients. PFS2 favored combination therapy (HR = 0.77; 95% CI: 0.64–0.91). Grade ≥3 AEs were more frequent (RR = 1.44; 95% CI: 1.20–1.73). Monotherapy improved rPFS in ITT (HR = 0.46; 95% CI: 0.20–0.81) and BRCAm (HR = 0.33; 95% CI: 0.15–0.75); OS benefit was seen only in BRCAm (HR = 0.73; 95% CI: 0.57–0.95). Conclusions: PARPi therapies improve outcomes mainly in HRR- and BRCA-mutated mCRPC. Molecular selection is key to optimizing benefit and minimizing toxicity. Further research on the activity of PARPi combinations in non-HRR mutated mCRPC is needed to better understand the underlying mechanisms of efficacy. Full article

Background: PSMA PET/CT imaging has become a cornerstone in the management of prostate cancer, particularly in the setting of biochemical recurrence (BCR). While semi-quantitative parameters such as SUVmean have been evaluated as prognostic biomarkers in metastatic castration-resistant prostate cancer (mCRPC), particularly after the VISION trial, the prognostic role of volumetric measures such as Total Molecular Volume (TMV) remain largely unexplored, especially in earlier stages of the disease such as in biochemical recurrence following primary treatment. Methods: This retrospective monocentric study included 84 patients with BCR who underwent PSMA PET/CT imaging between 2020 and 2021 using either [⁶⁸Ga]Ga-PSMA-11(Ga-PSMA) or [¹⁸F]-PSMA-1007 (F-PSMA) as tracers. Total tumor burden was assessed through manual 3D segmentation to derive whole-body Total Molecular Volume (wb TMV) and Total Lesion PSMA (wb TL-PSMA). Clinical and imaging variables were correlated with overall survival (OS) and progression-free survival (PFS) using Cox regression models. Kaplan–Meier analyses were performed based on wb TMV and thresholds determined by the Youden index. Results: A PSMA PET/CT correlation for BCR was identified in 69% of patients, with comparable detection rates between tracers (Ga-PSMA 67% vs. F-PSMA 63%, p = 0.7). A higher wb TMV was significantly associated with worse OS (HR 2.20, p < 0.001) and PFS (HR 2.01, p < 0.001) in univariable analyses. In multivariable models, log₂(wb TMV) remained an independent prognostic factor for PFS (HR 1.78, p = 0.005). Patients with log₂(wb TMV) > 2.87 exhibited significantly poorer survival outcomes. A PSA at diagnosis > 17 ng/mL also predicted shorter PFS. Conclusions: Tumor segmentation from PSMA PET/CT imaging provides powerful prognostic information in patients with biochemical recurrence of prostate cancer, independently of the tracer used. The wb TMV represents a promising volumetric biomarker for future risk stratification and therapeutic decision-making, particularly in earlier stages of prostate cancer progression, where predictive imaging biomarkers remain largely undefined. Full article

Background: Radioligand therapy with [¹⁷⁷Lu]Lu-PSMA-617 represents an emerging treatment for metastatic castration-resistant prostate cancer (mCRPC). Its clinical positioning relative to standard therapies remains under discussion. Objective: To compare overall survival (OS), radiographic progression-free survival (rPFS), PSA response, and treatment burden across randomised trials evaluating [¹⁷⁷Lu]Lu-PSMA-617 versus androgen receptor pathway inhibitors (ARTA), Cabazitaxel, or standard of care (SOC). Evidence Acquisition: We conducted a meta-analysis of five randomised controlled trials, including 2073 patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). We assessed survival endpoints, baseline comparability, and treatment intensity. Evidence Synthesis: [¹⁷⁷Lu]Lu-PSMA-617 significantly improved rPFS and PSA response. While modest overall, the OS benefit was more pronounced in taxane-naïve populations. Compared with Cabazitaxel, [¹⁷⁷Lu]Lu-PSMA-617 was associated with similar or better survival despite shorter treatment duration and potentially lower cumulative toxicity and cost. Economic modelling suggests it could offer a more sustainable therapeutic option under typical willingness-to-pay thresholds. Conclusions: [¹⁷⁷Lu]Lu-PSMA-617 shows clinical effectiveness and economic value in mCRPC, with potential advantages over Cabazitaxel and ARTA. Its use could be prioritised in early treatment lines. Patient Summary: This study suggests that PSMA-targeted radioligand therapy is at least as effective as other treatments for advanced prostate cancer, with potential benefits in terms of toxicity, duration, and overall cost. Full article

Prostate cancer (PCa) is a highly heterogeneous disease, with castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC) representing its most aggressive and therapy-resistant forms. Emerging evidence indicates that lineage plasticity—driven by key transcription factors such as Octamer Binding Factor 4 (OCT4)—plays a crucial role in therapeutic resistance and disease progression. OCT4, in coordination with SOX2 and NANOG, acts as a master regulator of stemness and is frequently upregulated in prostate cancer stem cells (PCSCs). This upregulation contributes to tumor initiation, metastasis, and resistance to both androgen deprivation therapy (ADT) and chemotherapy. In this review, we explore the role of OCT4 in mediating lineage plasticity in prostate cancer, with particular emphasis on its involvement in treatment resistance and neuroendocrine differentiation. We also examine therapeutic strategies aimed at targeting OCT4 directly, such as microRNA-mediated suppression, small-molecule inhibitors, and suicide gene therapy, as well as indirect approaches that modulate OCT4 expression via FGFR and NF-κB signaling pathways. While these strategies offer promising avenues, challenges such as adaptive resistance and the intricate signaling networks within PCSCs remain significant hurdles. A deeper understanding of the molecular mechanisms underlying OCT4-driven plasticity may pave the way for novel therapeutic approaches and improved outcomes in advanced prostate cancer. Full article