Search Results (287)

Background and Objectives: Overweight and obesity is defined as a Body Mass Index (BMI) of 25.0–29.9 kg/m² and ≥30.0 kg/m². The prognostic significance of obesity in metastatic prostate cancer is still unclear, especially between the castration-sensitive (CSPC) and castration-resistant (CRPC) disease states. New evidence suggests that obese patients who get androgen receptor–targeted therapies may have an unexpected survival advantage. This study examined the correlation between body mass index (BMI) and survival outcomes in patients administered androgen receptor pathway inhibitors. Materials and Methods: A retrospective analysis was conducted on a cohort of 167 patients with metastatic prostate cancer treated between 2015 and 2024. BMI was analyzed as both a continuous variable and a categorical variable, which was classified as normal weight, overweight or obese. The primary goal of this study is to compare PFS and OS among BMI groups. We employed Kaplan–Meier survival analysis and Cox regression modeling to evaluate prognostic indicators. The CSPC and CRPC groups were evaluated separately. Results: PFSs for normal, overweight and obese CSPC patients were 11.3, 15.1, 19.5 months, respectively; p = 0.03 but the OS did not differ significantly between BMI groups. OS for normal, overweight and obese CRPC patients were 32.8, 47.6 and 43.4 months, respectively; p = 0.01. There was also a trend toward better PFS, but it was not statistically significant. Multivariate analysis found that obesity (BMI ≥ 30) was a separate protective factor for PFS in CSPC, while high-volume disease was a bad prognostic factor for OS in CRPC. A high Gleason score and ECOG-PS 2 were consistently associated with poor outcomes. Conclusions: Obesity has a phase-dependent prognostic influence in metastatic prostate cancer, providing a PFS advantage in CSPC and an OS benefit in CRPC. These results suggest that there may be an obesity paradox in people who are getting androgen receptor–targeted therapy. Further prospective studies are required to gain a better understanding of the biological reasons for this association. Full article

Background: Although the relationship between androgen deprivation therapy (ADT) for prostate cancer (PC) and the biological mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains unequivocally unclear, it is possible that exposure to the virus may influence PC evolution by altering TMPRSS2 expression. This study aims to evaluate the long-term oncological outcomes of patients with metastatic PC who were undergoing medical therapy at the time of contracting SARS-CoV-2 and who resumed/continued anticancer treatment after recovery. Methods: We retrospectively evaluated a consecutive series of 151 metastatic PC patients who developed SARS-CoV-2 infection while receiving one active systemic anticancer therapy (125 metastatic castration-resistant PC (mCRPC) patients and 26 metastatic hormone-sensitive PC (mHSPC) patients). We evaluated variables that influence the ability to maintain or resume the ongoing therapy. For the maintained/resumed therapies, we calculated the post-infection overall survival (piOS) and the overall survival (OS). Results: Of the patients, 12.6% died due to SARS-CoV-2 infection, 10.6% recovered from the infection but failed to maintain/resume the ongoing anticancer treatment, and the remaining 76.8% maintained/resumed the treatment after recovery. Hospitalization, duration of infection, and the type of ongoing anticancer agent influenced these treatment changes. In the cohort of mCRPC patients, the median piOS was 32 months, and the median OS was 67.8 months. The median piOS was not achieved in the cohort of mHSPC patients, while the median OS was 122 months. The outcomes of single anticancer agents were in line with those of pivotal trials. Conclusions: Although observed in a highly selected population of PC patients who survived SARS-CoV-2 infection and were able to resume/maintain anticancer therapy, the survival outcomes of this study appear to be in line with those reported in pivotal studies, and SARS-CoV-2 infection does not seem to have adversely affected long-term oncological outcomes. Full article

Prostate cancer is one of the most common malignancies in men, and advanced or metastatic disease remains associated with substantial morbidity and mortality. Therapeutic progress in recent years has been driven by the introduction of targeted treatment strategies, notably poly (ADP-ribose) polymerase (PARP) inhibitors, prostate-specific membrane antigen (PSMA)–directed radioligand therapy (RLT), and androgen receptor pathway inhibitors (ARPIs). This review summarizes evidence from phase II and III clinical trials, meta-analyses, and real-world studies evaluating the efficacy, safety, and clinical integration of olaparib, lutetium (¹⁷⁷Lu) vipivotide tetraxetan, and abiraterone in advanced prostate cancer. Emphasis is placed on the practical clinical application of these agents, including patient selection, treatment sequencing, and combination strategies. PARP inhibition with olaparib has demonstrated clear benefits in metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) mutations, particularly BRCA1/2 alterations. PSMA-directed RLT offers a survival advantage in PSMA-positive mCRPC following AR pathway inhibition, with distinct toxicity considerations that influence patient selection. Abiraterone remains a cornerstone therapy across disease stages and plays an important role both as monotherapy and as a combination partner. Emerging data suggest a potential synergy between PARP inhibitors and AR-targeted agents, while also highlighting the limitations of biomarker-unselected approaches. We conclude that the optimal use of PARP inhibitors, PSMA-targeted RLT, and ARPIs requires a personalized strategy guided by molecular profiling, functional imaging, prior treatment exposure, and safety considerations. This clinically focused overview aims to support evidence-based decision-making in an increasingly complex treatment landscape. Full article

Prostate cancer (PCa) is the leading cause of cancer-related deaths worldwide and the second most common cancer among men. Treatment options depend on factors like age, androgen sensitivity, PSA levels, Gleason score, TNM stage, and recurrence risk. Available treatments include hormonal therapy, radiation, surgery, and chemotherapy. Early immunological treatments were limited by poor lymphocyte infiltration and an immunosuppressive environment. Today, strategies such as dendritic cell vaccines, immune checkpoint inhibitors (ICIs), and adoptive cell therapy (ACT) are used. ACT, especially CAR T-cell strategies, aims to overcome traditional treatment limitations, particularly in advanced and metastatic castration-resistant prostate cancer (mCRPC), though it remains in early development. Personalized medicine uses molecular insights from the diseased tissue to tailor treatments. Variability in patient response, due to tumor heterogeneity and prior treatments, highlights the importance of personalized and combination therapies as future strategies for effective immunotherapy. This review explores the current landscape of PCa. We analyze treatment guidelines established by NCCN and EANM-ESTRO-ESUR-ISUP-SIOG. We comprehensively examine immunotherapeutic strategies currently available or under investigation for prostate cancer, with particular emphasis on ICIs, ACT with a focus on CAR T-cell therapy, combination approaches and therapeutic synergies, and predictive biomarkers of immunotherapy response. Additionally, we discuss the challenges and future directions in the implementation of immunotherapy for the management of prostate cancer. Full article

Circulating tumor DNA (ctDNA) analysis has emerged as a powerful and minimally invasive approach for genomic profiling of metastatic castration-resistant prostate cancer (mCRPC), enabling real-time detection of tumor-derived mutations that guide therapy. Approximately 20% of mCRPC patients harbor alterations in homologous recombination repair (HRR) genes, most commonly BRCA1/2 and ATM, which are actionable with different poly-(ADP-ribose) polymerase inhibitors (PARPIs) used as monotherapy or in combination with androgen receptor signaling inhibitors (ARSIs). A smaller subset of patients with mismatch repair deficiency (MMRd) or microsatellite instability-high (MSI-high) tumors may benefit from immune checkpoint blockade with pembrolizumab. Different FDA-approved liquid biopsy assays detect these actionable alterations when tissue biopsies are unavailable or insufficient. This review summarizes current evidence on ctDNA-based genotyping in mCRPC, highlighting clinically actionable mutations, corresponding targeted therapies, and technical and analytical considerations for clinical implementation. By capturing DNA shed from multiple metastatic sites, ctDNA profiling provides a comprehensive view of tumor heterogeneity and enables serial monitoring of molecular evolution. Overall, ctDNA analysis represents a transformative advance in precision oncology, supporting personalized treatment selection and ongoing assessment of therapeutic response in mCRPC. Full article

Castration-resistant prostate cancer (CRPC) remains a major clinical challenge, with disease progression frequently occurring despite the use of potent androgen receptor (AR)-targeted therapies. As AR signalling continues to drive tumour growth in this setting, new therapeutic strategies are being developed to disrupt the AR axis through both direct and indirect mechanisms. This review highlights a selection of promising agents in preclinical or clinical development that represent the next generation of therapies targeting AR signalling. Direct approaches include novel agents that degrade the AR or target domains beyond the conventional ligand-binding domain, aiming to overcome resistance to existing anti-androgens. Indirect strategies are designed to interfere with AR function by modulating AR-associated transcriptional co-regulators, chromatin accessibility, and other regulatory proteins, such as splicing factors, that are critical for sustaining AR-driven gene expression in prostate cancer. Together, these therapies form the basis of emerging strategies to more effectively suppress AR activity in CRPC. This review discusses AR-activating mechanisms, the mechanisms of action of these agents, their clinical development status, and their potential to reshape future treatment paradigms in CRPC. Full article

Background/Objectives: Metastatic castration-resistant prostate cancer (mCRPC) remains a major clinical challenge due to its aggressive behavior and resistance to therapy. Survivin, a member of the inhibitor of apoptosis protein family, is overexpressed in various cancers and associated with poor prognosis. YM155 (Sepantronium bromide) suppresses survivin expression and has demonstrated antitumor activity in preclinical models. We investigated the association between survivin expression and clinical outcomes in mCRPC patients and evaluated the antitumor activity of YM155, alone and in combination with carboplatin, in mCRPC cell lines. Methods: Analysis of publicly available RNA-seq datasets from mCRPC patients was performed to assess correlations between survivin expression and clinical outcomes. Radiographic progression-free survival (rPFS) and overall survival (OS) were estimated using the Kaplan–Meier method and compared via log-rank or Fisher’s exact tests. In vitro assays were conducted on mCRPC cell lines treated with YM155, carboplatin, or both, to evaluate cell viability, clonogenicity, and apoptosis. Results: Survivin was significantly overexpressed in mCRPC compared with localized prostate cancer and was even higher in castration-resistant neuroendocrine disease. High survivin levels were associated with shorter OS (p = 0.006). In patients treated with platinum-based therapies, high survivin was also linked to shorter rPFS (p = 0.01), reduced OS (p = 0.006), and a smaller PSA decline (p = 0.006). In vitro, YM155 reduced survivin expression, impaired cell viability and colony formation, induced apoptosis, and synergistically enhanced the cytotoxicity of carboplatin. Conclusions: Our findings suggest that survivin may serve as a prognostic biomarker and potential therapeutic target in platinum-treated, AR-independent mCRPC. The integration of clinical and functional data provides translational support for combining the survivin inhibitor YM155 with platinum-based therapy. These results warrant further validation in larger patient cohorts and in vivo models. Full article

Background: To clarify the timing of treatment initiation for non-metastatic castration-resistant prostate cancer (nmCRPC), we investigated the impact of baseline prostate-specific antigen (PSA) at treatment initiation on outcomes, the stability of PSADT estimation at low PSA levels, and the prognostic significance of PSADT. Methods: We retrospectively analyzed 129 consecutive nmCRPC patients between 2000 and 2023. All patients were divided by PSADT ≤ 10 months (n = 109) or >10 months (n = 20). PSA progression-free survival (PSA-PFS) and metastasis-free survival (MFS) were assessed by the Kaplan–Meier method, with predictive factors analyzed using Cox proportional hazards modeling. PSA-PFS was further compared across baseline PSA subgroups (<3, 3–5, 5–10, >10 ng/mL) in the PSADT ≤ 10 months cohort. Results: Patients with PSADT ≤ 10 months had worse MFS than patients with PSADT > 10 months (4-year: 71.9% vs. 100%; p = 0.021). In the PSADT ≤ 10 months group, novel androgen receptor pathway inhibitor (ARPI) treatment significantly improved PSA-PFS compared to those who did not (median: 44.0 vs. 16.6 months; p < 0.001). In multivariate analysis, prior definitive local therapy (Hazard Ratio [HR] 0.409, p < 0.001), ARPIs as first-line treatment (HR 0.421, p < 0.001) and lower baseline PSA at treatment initiation (HR 0.961, p = 0.004) were significantly predictive factors for PSA-PFS. PSADT estimation remained accurate when calculated from PSA nadir values ≥0.5 ng/mL. Conclusions: In patients with nmCRPC with PSADT ≤ 10 months, early initiation of ARPIs at lower PSA levels was associated with improved PSA-PFS. PSADT stabilized at PSA levels of >0.5 ng/mL. These findings support earlier ARPI initiation to optimize outcomes in high-risk nmCRPC. Full article

Metastatic castration-resistant prostate cancer/PCa (mCRPC) is a clinically advanced form of PCa that is associated with increased aggressiveness, cancer stemness, morbidity, and the risk of developing resistance to taxanes, currently the first-line chemotherapy for mCRPC. Clofazimine (CLF) is a potential immunomodulator drug that is FDA-approved for the treatment of leprosy. Recently, using in vitro, in vivo, and ex vivo models, we established the efficacy of CLF in chronic myeloid leukemia and multiple myeloma. Here, we demonstrate that CLF is effective as a single agent and in combination with taxanes in a panel of cell lines representing the diversity of CRPC patients. Using a microfluidic assay, we showed the impact of CLF on cancer cell migration and metastatic potential. Further, we also found that CLF reduces ALDH activity—a marker for cancer ‘stem-like’ cells (CSCs), a subtype of cancer cells with self-renewal and differentiation capacities (epithelial-to-mesenchymal transdifferentiation/EMT). Bulk and single-cell RNAseq followed by functional validation and in silico analysis showed that CLF treatment is associated with apoptosis, ER stress, oxidative phosphorylation, and mitochondrial dysfunction. Most importantly, CLF modulates the expression of several non-coding RNAs, including MALAT1 and NEAT1, that are linked to tumor cell proliferation, cell migration, and drug resistance. Full article

Background/Objectives: To investigate the efficacy and safety of treatment with [¹⁷⁷Lu]Lu-PSMA-I&T Radioligand Therapy (PSMA-RLT) in older patients (≥80 years) vs. younger ones with metastatic castration-resistant prostate cancer (mCRPC). Methods: In this retrospective single-center analysis, 103 patients treated with PSMA-RLT between 2019 and 2024 were included. Overall survival (OS) and therapeutic response were assessed by PSA serum and based on PET/CT Imaging according to the RECIP 1.0 criteria, respectively. Toxicity was additionally assessed via laboratory (hemoglobin, cell counts, and serum creatinine). Adverse events (AEs) were detected according to CTCAE V.5. Results: Median OS did not differ significantly in patients ≥ 80 years vs. <80 years (13.7 vs. 16.1 months, respectively). PSA decline of ≥50% was achieved in 32% patients in total, comparably in both groups (29.4% vs. 34.8%). According to RECIP 1.0, the majority of patients with both ≥80 and <80 years demonstrated stable disease or partial responses in imaging (64% and 71%, post two cycles). Concerning toxicity, the most frequently observed AE was anemia, which occurred in both <80 and ≥80 subgroups (grade 3: 2.8% vs. 5.9%); however, no grade 4 anemia was recorded. Renal function remained stable throughout treatment, and no AE grade 3 or higher was observed. Overall, the safety profile was comparable between age groups. Conclusions: Treatment with PSMA-RLT can be both effective and well tolerated in patients with mCRPC aged 80 years and older. Full article

Prostate-specific membrane antigen (PSMA) targeting agents have been the cornerstone of advanced prostate cancer (PCa) management in theranostics due to their high sensitivity for detecting and treating metastatic disease. However, approximately one-third of metastatic castration-resistant PCa (mCRPC) lesions may exhibit low or absent PSMA expression due to tumor heterogeneity, prior androgen deprivation therapy, or loss of androgen receptor expression, subsequently altering their response to PSMA-targeted therapy. The molecular and biological mechanisms underlying PSMA downregulation remain elusive but may include neuroendocrine differentiation or epithelial-to-mesenchymal transition (EMT). This review addresses this knowledge gap by examining recent preclinical and clinical evidence on novel radiotracers with the potential to provide alternative strategies beyond PSMA for imaging and treating PCa. The diagnostic performance and therapeutic potential of three emerging radiotracer classes are discussed, including gastrin-releasing peptide receptor (GRPR) ligands, androgen receptor (AR) ligands, and amino acid analogs. This article further highlights the complementary roles of these radiotracers along with their utility in specific patient populations, such as those with low prostate-specific antigen (PSA), biochemical recurrence (BCR), or confirmed PSMA-negative disease. For instance, GRPR-targeted radiotracers have achieved sensitivity of up to 88% and specificity of up to 90% for detecting primary tumors in PCa. The radiolabeled androgen agonist, fluorine-18 (¹⁸F)-fluoro-5α-dihydrotestosterone (FDHT), has demonstrated 98% true-positive rate in predicting lesions on positron emission tomography (PET) scans of mCRPC patients. On the other hand, the synthetic amino acid analog ¹⁸F-fluciclovine demonstrated a lesion detection rate of 84% for PSA levels at or above 5, and 62.5% for PSA levels ranging from 0.7 to less than 1. This review concludes with future directions on the paradigm of multi-tracer and dual-targeting strategies, which can effectively address challenges associated with PCa tumor heterogeneity and facilitate personalized approaches in theranostics. Full article

Despite advances in diagnostic and therapeutic technology, prostate cancer remains a leading cause of morbidity and mortality among men. While androgen deprivation therapy and next-generation androgen receptor pathway inhibitors offer durable responses, the emergence of the lethal phenotype, metastatic castration-resistant prostate cancer (mCRPC) eventually develops for most. A growing body of evidence points to the tumor microenvironment (TME) as a key driver of immune evasion and therapeutic failure. This review focuses on the current knowledge of immune suppression in the prostate TME, including cancer-associated fibroblasts, myeloid-derived suppressor cells, tumor-associated macrophages, immune checkpoint pathways, and several associated key metabolic alterations. These cellular and molecular networks contribute to therapeutic resistance and disease progression and may be used as therapeutic targets. We will also examine emerging treatment strategies aimed at reprogramming the TME, as well as combination approaches incorporating immunotherapies with other signaling inhibitors. Future success in clinical therapeutic development for mCRPC will depend on rational combinations that address both tumor-intrinsic resistance and extrinsic immune suppression, with emphasis on biomarker-driven patient and treatment selection. Full article

Elevated cholesterol levels play important mitogenic roles. Pseurotin A (PsA) is a fermentation product that has recently been reported as a dual inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) secretion and protein-protein interaction (PPI) with the LDLR. PsA showed a high acute safety profile and therapeutic potential against metastatic castration-resistant prostate cancer (mCRPC). The study aims to uncover the chronic safety, distribution, and anti-mCRPC genomic and molecular mechanistic insights of PsA. A 90-day chronic safety assessment of PsA up to 80 mg/kg in Swiss albino mice showed no signs of hematological, biochemical, or major organ toxicity. PsA demonstrated rapid intravenous distribution and elimination in Swiss albino mice. PsA is biodistributed to multiple key organs but was not detected in the brain, indicating its inability to cross the blood-brain barrier. PsA effectively suppressed the recurrence of nude mice xenografted mCRPC, which was subjected to a neoadjuvant docetaxel and enzalutamide regimen, followed by surgical excision. Collected PsA and vehicle control-treated recurrent tumors were subjected to RNA-sequencing and pathway enrichment analysis (PEA) of differentially expressed genes (DEGs). PsA-treated tumors revealed multiple significantly enriched pathways associated with promoting tumor apoptosis and inhibiting both invasion and migration. The PPI network analyses for the downregulated DEGs displayed prominent networks of genes associated with the ubiquitin-proteasome system. Results provide comprehensive mechanistic and preclinical validations for PsA’s potential as a novel PC recurrence suppressive lead entity. Full article

A group of Spanish experts of different specialties participated in the ENFOCA2 project, promoted by the Spanish Oncology Genitourinary Group (SOGUG), which was designed to provide updated information on current and novel aspects contributing to the optimal care of prostate cancer (PCa) patients. In localized disease, it is important to implement strategic alliances with other institutions for improving adherence to active surveillance in low-risk groups and to explore genetic testing for a better indication of focal therapy. Local control of the disease should be maximized to prevent local failure and biochemical recurrence. In patients with locally advanced disease, with PSMA PET/CT-positive lesions in M0 staging on conventional imaging techniques, therapeutic decisions should be carefully evaluated due to insufficient evidence regarding the gold standard in this setting. In patients with metastatic castration-resistant PCa (mCRPC), assessment of BRCA somatic and germline mutations provides prognostic information and familial cancer risk and informs treatment decisions. Combinations of androgen receptor signaling inhibitor (ARSi) agents and poly-ADP ribose polymerase inhibitors (PARPi) are emerging alternatives for advanced PCa. The oldest segment of PCa patients (>70 years of age) may require geriatric assessment to evaluate physical and functional reserves, tailoring treatment to their individual characteristics and circumstances. The concept of a comprehensive multidisciplinary approach together with inter-center and/or inter-specialty therapeutic alliances should be implemented in the routine care of patients with PCa. Full article

Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor approved for treating metastatic castration-resistant prostate cancer (mCRPC) with BRCA mutations, has significant clinical benefits. However, evidence suggests an increased risk of venous thromboembolism, including pulmonary embolism (PE), particularly in patients with PC. However, no case reports of olaparib-associated PE in mCRPC have been published. Here, we report the case of a 70-year-old man with mCRPC harboring a BRCA2 mutation, who developed PE during olaparib therapy. Diagnostic evaluations included contrast-enhanced computed tomography and serum D-dimer level measurement. Clinical decision tools, such as the Wells score and the Khorana score, were used to support the diagnosis and risk assessment. The patient developed acute dyspnea and chest pain 7 months after olaparib initiation. Imaging confirmed multiple pulmonary emboli; laboratory testing revealed markedly elevated D-dimer levels. Anticoagulation therapy with apixaban led to rapid clinical and radiological improvement. However, mCRPC eventually progressed after olaparib discontinuation, and the patient died 15 months after olaparib initiation. This is the first reported case of olaparib-associated PE in mCRPC. It underscores the importance of vigilance for thromboembolic complications during PARP inhibitor therapy. The integration of clinical scoring systems and biomarkers may facilitate timely PE diagnosis and management, potentially improving patient outcomes. Full article