BACKGROUND:Focal irreversible electroporation (IRE) is an attractive choice for patients aiming to obtain local control of prostate cancer, while decreasing the postoperative risk of impotence and incontinence compared to whole-gland treatments. METHODS:Retrospective review of a single centre prospective database of 171 consecutive primary IRE procedures for localised prostate cancer. Primary outcomes include oncological infield and out-of-field progression. Secondary objectives include post-IRE continence and impotence. RESULTS:The median follow-up is 35 months (3-90 months). The median diameter of the treated lesions is 11 mm (4-24 mm). Most patients had PI-RADS 4-5 abnormalities on prostate MRI, and 25 patients (15%) had ISUP grade 4-5 cancer. Of the 135 patients with >12 months follow-up, 84 had a surveillance biopsy of whom 8.3% had significant infield persistence, with significant out-of-field cancer in 14.3%. There was no difference in the risk of infield cancer persistence regardless of the pre-IRE ISUP score (p = 0.8), or tumour location (p > 0.9). The presence of low volume out-of-field cancer at diagnosis did not increase the risk of post-IRE cancer persistence/progression (p = 0.7). The prostate PSMA PET SUVmax of ≥10 did not increase the risk of infield or out-of-field recurrence of cancer (p = 0.3). A PSAD > 0.15 did not increase the risk of infield persistence or out-of-field progression of cancer (p = 0.8). Urinary continence was maintained in 167/171 (97.6%), while erectile function was maintained in 94/112 (84%) of sexually active patients who completed questionnaires. CONCLUSIONS:Of the patients who proceeded to post-IRE biopsy, 92% had infield ablation of clinically significant cancer with a low risk of urinary incontinence or impotence. Focal IRE of prostate cancer has promising short to medium-term outcomes and is associated with low risks of impotence and incontinence. Long-term follow-up of out-of-field progression risk is required.
BACKGROUND:Second-generation androgen receptor pathway inhibitors (ARPIs) have transformed treatment for patients with advanced prostate cancer. Despite overlapping indications and comparable efficacy among these ARPIs, their staggered market entry and differing toxicity profiles may influence real-world prescribing. We characterized temporal trends and utilization patterns of these agents as frontline treatment for advanced prostate cancer in the United States. METHODS:Using the Merative MarketScan database, we identified patients with prostate cancer receiving enzalutamide, apalutamide, or darolutamide between 2012 and 2023. ARPI therapy was classified as first-line if initiated after ≥180 days of continuous enrollment. Annual proportions of first-line initiation and overall utilization of ARPIs were assessed descriptively. Comparisons by geographic status, urbanicity, insurance plan, and metastatic status were evaluated using chi-squared testing and multivariable modeling. RESULTS:Among 1.1 million individuals with prostate cancer, 3773 patients received ARPI therapy, of whom 1914 met criteria for first-line analysis. Use of first-line darolutamide steadily increased, rising to 42% in 2023 and surpassing enzalutamide. First-line ARPI selection did not differ significantly by region, urbanicity, insurance, or metastatic status. Overall ARPI utilization increased 21-fold over the study period, with enzalutamide remaining the most common agent. In 2023, a higher proportion of darolutamide fills occurred in metropolitan areas (p = 0.0008), and among metastatic patients (p = 0.0058). CONCLUSION:Darolutamide rapidly emerged as the most selected first-line ARPI by 2023, without consistently observed differences by patient demographics. However, continued dominance of enzalutamide for overall fills may highlight durability of legacy therapy, particularly among non-metropolitan and non-metastatic populations.
BACKGROUND:Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease state with limited durable responses to existing therapies, including taxane-based chemotherapy. Resistance mechanisms are multifactorial and incompletely addressed by current treatments. Drug repurposing offers an accelerated pathway for the development of novel therapeutic strategies in treatment-resistant disease. METHODS:This review synthesizes preclinical mechanistic data and clinical experience with itraconazole (ITZ), a clinically approved triazole antifungal, across prostate cancer and other malignancies. We evaluate the signaling pathways targeted by ITZ, barriers to its clinical translation, and opportunities for biomarker-driven combination therapy. RESULTS:ITZ functions as a pleiotropic anticancer compound that modulates multiple pathways implicated in prostate cancer progression and therapeutic resistance, including Hedgehog/GLI, PI3K/AKT/mTOR, and Wnt/β-catenin signaling, as well as drug efflux transporters. Preclinical studies demonstrate that ITZ reverses ABCB1-mediated docetaxel resistance, suppresses Hedgehog/GLI1 signaling, and inhibits cancer cell proliferation and invasion. Despite compelling mechanistic rationale, clinical activity in mCRPC has been modest, with limited durable responses, underscoring a translational disconnect. Advancement of ITZ into clinical practice is constrained by pharmacokinetic challenges, dose-limiting toxicities, and the lack of validated predictive biomarkers to identify responsive patient subsets. Emerging evidence further suggests potential synergy with immune checkpoint inhibitors through tumor microenvironment modulation, though this remains unexplored in prostate cancer. CONCLUSIONS:ITZ represents a potential adjunctive strategy to standard therapies within rationally designed, biomarker-stratified combination regimens for mCRPC. Target populations include patients with PTEN-null tumors (elevated Hh/GLI and PI3K/AKT signaling), ABCB1-overexpressing tumors (taxane resistance), or those progressing after AR pathway inhibitor therapy. Clinical advancement will require pharmacological optimization, development and validation of patient stratification biomarkers (GLI1/PTCH1, PTEN status, ABCB1 expression), and integration with therapies targeting complementary resistance pathways.
BACKGROUND:Identifying clinical and genomic predictors of response to androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPI) for metastatic androgen pathway modulator sensitive (APMS) prostate cancer is essential for improving therapeutic decision-making. Divergent outcomes are observed in practice, with some achieving exceptional responses (ER) while others experience early resistance or non-response (NR), the biologic basis of which remains unclear. METHODS:A retrospective review was conducted of patients with APMS prescribed ADT/ARPI from 2015-2024. ER and NR were defined by upper ( > 53.36 months) and lower ( < 10.41 months) quartiles of progression-free survival (PFS). Objectives were to associate baseline genomic and clinical factors with ER/NR status, PFS, overall survival (OS) and PSA kinetics.. RESULTS:Among 3363 prescribed ADT/ARPI, 224 were treated for APMS, with 154 (69%) undergoing temporal molecular testing. Alteration of ≥1 tumor suppressor gene with or without proliferative gene co-alteration was associated with NR while no single alteration predicted achieving ER. ECOG < 1, lack of pain, low-volume disease, higher hemoglobin and albumin, and normal alkaline phosphatase were associated with improved PFS, OS, and PSA nadir <0.2 ng/mL at 12 months. Alterations in TP53 (HR 1.60 [95%CI 1.02-2.50], p = 0.039; HR 1.91 [95%CI 1.05-3.49], p = 0.035) and MYC (HR 2.01 [95%CI 1.03-3.91], p = 0.040; HR 3.81 [95%CI 1.81-7.99], p < 0.001) were associated with inferior PFS and OS, while BRCA2 (HR 2.12 [95%CI 1.02-4.42], p = 0.045) additionally associated with PFS, and RAD21 (HR 2.55 [95%CI 1.13-5.77], p = 0.024) with OS. On multivariable analysis, MYC gain associated with OS (HR 4.41 [95%CI 1.24-15.7], p = 0.022). Pathway-level analysis showed proliferative gene alterations were associated with failure to achieve PSA nadir <0.2 ng/mL at 12 months (HR 0.49 [95%CI 0.24, 0.98], p = 0.047). CONCLUSIONS:In this real-world APMS cohort, we identified pre-treatment clinical and genomic predictors of patient benefits and long-term survival with ADT/ARPI therapy.
BACKGROUND:Multiple germline variants are associated with prostate cancer (PCa) susceptibility and aggressive features; however, their value for predicting prostate cancer-specific mortality (PCSM) at the time of diagnosis remains uncertain, particularly among men with clinically localized disease. METHODS:We evaluated associations between germline risk factors and PCSM among 14,644 men with incident PCa in the UK Biobank. Associations between PCSM and reported germline risk factors, including 11 genes recommended by the National Comprehensive Cancer Network (NCCN), nine other candidate genes, two common variants [KLK3 (I179T) and HSD3B1 (1245 A > C)], and three polygenic risk scores (PRSs), were tested using Fine-Gray competing-risk models accounting for non-PCa mortality. RESULTS:During a median follow-up of 6.73 years after diagnosis, 1581 men (10.8%) died from PCa. PVs in three NCCN-recommended DNA damage-repair genes (BRCA2, MSH6, PALB2) were individually associated with increased PCSM and were defined as Tier-1. Aggregated PVs in seven additional NCCN-recommended DDR genes (Tier-2) and the KLK3 I179T variant were also independently associated with PCSM. In contrast, HOXB13, nine other candidate genes, HSD3B1, and all three PRSs were not associated with cumulative PCSM risk. Overall, 14.45% of men carried Tier-1 or Tier-2 PVs and/or KLK3 I179T and experienced significantly earlier PCa-specific mortality. Importantly, associations remained significant among men without metastatic disease at diagnosis. CONCLUSIONS:Reported inherited susceptibility to PCa does not uniformly confer risk of lethal progression. Germline PVs in NCCN-recommended DDR genes and the KLK3 I179T variant identify a subset of men at elevated risk of PCSM, including those with apparently localized disease. These findings support consideration of selected germline markers for prognostic risk stratification at diagnosis to inform individualized management decisions.
BACKGROUND:Cribriform pattern (CP) and intraductal carcinoma of the prostate (IDC-P) are recognised as adverse histopathological markers. However, their precise prognostic weight in the post-radical prostatectomy (RP) setting remains poorly standardised. We performed a systematic review and meta-analysis to quantify the association between CP/IDC-P and biochemical recurrence (BCR). METHODS:A systematic search of MEDLINE, Scopus, and Web of Science was conducted for studies published from 2016 onwards, coinciding with the 2016 WHO and subsequent ISUP consensus recommendations. The primary endpoint was BCR. Hazard ratios (HR) were synthesised using random-effects models with restricted maximum likelihood (REML) estimation. RESULTS:Eight retrospective studies were eligible for quantitative synthesis. The cumulative prevalence of CP/IDC-P was 27%. On univariable analysis, CP/IDC-P was significantly associated with BCR (HR: 2.76; 95% CI: 2.23-3.41). This association remained robust in multivariable models adjusting for pathological stage and Grade Group (HR: 2.59; 95% CI: 1.44-4.67) and CAPRA-based preoperative frameworks (HR: 1.78; 95% CI: 1.03-3.08). Isolated CP demonstrated a more stable prognostic signal (HR: 3.16) compared to IDC-P (HR: 4.24), the latter being characterised by wider prediction intervals. The main limitations include the retrospective nature of primary studies and the inherent risk of confounding. CONCLUSIONS:CP and IDC-P are potent, independent predictors of BCR following RP. These findings support the mandatory reporting of such architectures according to ISUP standards and their integration into contemporary post-surgical risk-stratification algorithms to optimise follow-up and adjuvant therapy selection.
BACKGROUND:Grade Group 1 (GG1) prostate cancer is biologically indolent and typically managed with active surveillance (AS), yet pT3a pathology is occasionally identified at radical prostatectomy (RP). Its prognostic significance in GG1 disease remains incompletely defined. METHODS:Retrospective cohort of 40 patients with GG1 and pT3a disease on RP (2000-2022), confirmed on central pathologic re-review. RESULTS:Four patients developed biochemical recurrence (BCR); the cumulative incidence of BCR was 3.2% at 5 years and 10.3% at 15 years. No patient developed metastatic disease or prostate cancer-specific mortality. CONCLUSIONS:GG1 pT3a prostate cancer demonstrates excellent long-term outcomes. Adverse histologic features, not pathological stage alone, drive clinically meaningful risk. Late, stable PSA detectability alone does not signify meaningful recurrence.
PURPOSE:Smoking has been associated with increased metastatic prostate cancer mortality, but the mechanisms behind this are largely unknown. We hypothesized that smoking increases the risk of genetic alterations associated with aggressive disease and/or the transformation to neuroendocrine prostate cancer (NEPC). PATIENTS AND METHODS:We utilized the Prostate Cancer Precision Medicine Multi-institutional Collaborative Effort (PROMISE) clinical genomic database for this retrospective analysis. We associated patient characteristics and tumor genetic data with smoking exposure at diagnosis (current, former, never and pack years) and with clinical outcomes, including overall survival (OS) from diagnosis or time to developing metastatic disease and NEPC status. RESULTS:We identified 2353 men with prostate cancer and next generation somatic tumor sequencing evaluable for analysis in PROMISE, including 8% current, 39% former, and 52% never smokers. Current smokers were more likely to be younger and to have metastatic (M1 or N1) disease at diagnosis, and less likely to have prior local therapy (all p < 0.001). Current smoking was associated with worse OS from diagnosis (99.9 mo vs 137.6 mo, HR 1.42, 95% CI 1.14-1.77), which remained significant after adjusting for disease characteristics. We found no difference in the percentage of NEPC at initial diagnosis or at any time between current, former, and never smokers (p = 0.8). We found positive associations between smoking status and genetic alterations in SPOP (current: 15%, former 6.7%, never 3.8%; p = 0.018), FGFR1 (current 10%, former 0.4%, never 1.1% p = 0.001), and ARID1A (current 5.1%, former 2.2%, never 0.4%; p = 0.035) in patients with metastatic androgen pathway modulator sensitive prostate cancer (APMS). CONCLUSION:Active smoking is associated with worse overall and prostate cancer specific survival as compared to never/former smoking and was associated with specific tumor genetic alterations but not small cell/NEPC transformation.
BACKGROUND:Magnetic resonance imaging (MRI), introduced into European (2019) and Dutch (2020) guidelines, reshaped prostate cancer (PCa) diagnostics by altering biopsy indications and strategies. In expert-center studies MRI-based diagnostics reduces biopsy rates and ISUP Grade Group (GG) 1 detection, while maintaining or increasing GG ≥ 2 detection compared to systematic biopsies. We evaluated nationwide biopsy outcomes during MRI adoption in routine practice in the Netherlands. METHODS:Retrospective nationwide study of histopathology reports from all diagnostic biopsies in men without prior PCa in the Netherlands (2015-2021), retrieved from the Dutch nationwide pathology databank (Palga). Outcomes included annual biopsy volumes and proportions cancer-negative, GG1 and GG ≥ 2 biopsies. MRI-related terminology served as a proxy for MRI use. ISUP GG concordance between biopsy and radical prostatectomy (RP), defined as identical highest GG in biopsy and RP specimen, was assessed. The Mann-Kendall test evaluated monotonic time trends. RESULTS:Among 127,856 biopsies (116,711 men), annual diagnostic biopsy numbers decreased from 18,719 (2015) to 17,094 (2021; -8.7%, p = 0.13). Cancer-negative biopsies declined from 49% to 29% (p = 0.003), while GG ≥ 2 detection increased from 30% to 53% (p = 0.002). GG1 detection minimally decreased (20% to 18%, p = 0.02). MRI terminology in pathology reports increased (8.2% to 51%) and biopsy-RP GG concordance improved (51% to 60%, p = 0.007). Analyses could not adjust for increased opportunistic PSA screening or adjunct diagnostic tool use. CONCLUSIONS:Nationwide Dutch pathology data show improved diagnostic efficiency and efficacy over time, with fewer biopsies, fewer cancer-negative biopsies, and increased GG ≥ 2 detection. These findings coincide with rising estimated MRI uptake, suggesting MRI-driven diagnostic improvements.
BACKGROUND:Cardiovascular disease (CVD) is the leading cause of non-cancer mortality in prostate cancer (PCa) patients. The management of CVD, including hypertension, holds equal significance to cancer treatment. However, the optimal antihypertensive agent for blood pressure management in PCa patients receiving abiraterone acetate (AA) is still unclear. This study aims to investigate the association between various antihypertensive regimens and survival outcomes in PCa patients treated with AA. METHODS:We performed a post-hoc observational analysis using data from COU-AA-301 and COU-AA-302. Radiographic progression-free survival (rPFS), overall survival (OS) and prostate cancer-specific survival (PCSS) were evaluated using the Kaplan-Meier method. Cox proportional hazards models were used to obtain hazard ratios (HRs) and associated 95% confidence intervals (CIs). RESULTS:Among the AA groups of COU-AA-301 and COU-AA-302, angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) monotherapy was associated with longer rPFS (HR 0.82, 95% CI 0.59-1.13; HR 0.71, 95% CI 0.53-0.95), OS (HR 0.66, 95% CI 0.41-1.06; HR 0.70, 95% CI 0.53-0.92) and PCSS (HR 0.72, 95% CI 0.44-1.19; HR 0.67, 95% CI 0.49-0.92). Multiple-class antihypertensive treatment regimens including ACEI/ARBs were associated with longer rPFS (HR 0.74, 95% CI 0.59-0.92; HR 0.71, 95% CI 0.54-0.94), OS (HR 0.76, 95% CI 0.57-1.01; HR 0.72, 95% CI 0.55-0.94) and PCSS (HR 0.71, 95% CI 0.51-0.99; HR 0.62, 95% CI 0.46-0.83). Multivariable analysis indicated that ACEI/ARBs were associated with improved rPFS (HR 0.72, 95% CI 0.60-0.86; HR 0.75, 95% CI 0.60-0.94), OS (HR 0.71, 95% CI 0.56-0.91; HR 0.70, 95% CI 0.56-0.88) and PCSS (HR 0.73, 95% CI 0.55-0.96; HR 0.64, 95% CI 0.50-0.82). CONCLUSIONS:In this post-hoc analysis, concomitant use of ACEI/ARBs was associated with longer rPFS, OS and PCSS in PCa patients treated with AA. The potential role of ACEI/ARB-containing antihypertensive regimens in these patients warrants further investigation. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT00638690, NCT00887198.
BACKGROUND:Benign Prostatic Hyperplasia (BPH) affects more than half of men over age 50, yet current treatment options are limited to medications that cause bothersome side effects or surgical procedures, including minimally invasive surgical therapies (MIST) that involve piercing, cutting, or burning tissue, often leading to discomfort and recovery concerns. The Zenflow Spring System® provides a tissue-preserving alternative that offers symptom relief with quicker recovery and less procedural discomfort. METHODS:Three single-arm, multicenter, prospective pilot studies with similar trial designs were conducted from 2018-2021 across four countries and data were combined to evaluate the feasibility, safety, and effectiveness of the Spring System in relieving symptoms of obstructive BPH. Men ≥ 45 years with moderate-to-severe symptoms (International Prostate Symptom Score (IPSS ) >13), peak urinary flow rate (QMax) between 5 and 15 mL/s, prostate volume between 25 and 80 cc, prostatic urethral length between 25 and 45 mm, and voided volume of at least ≥ 125 mL were enrolled. The primary endpoint was symptom improvement 3 months post-procedure, measured by change in IPSS. Secondary endpoints included IPSS-QoL, and functional improvement measured by Qmax. Follow-up visits occurred through 24 months. RESULTS:Successful implantation of the Spring Implant was achieved in all 72 study participants, with no perioperative serious adverse events. At 3 months, mean change from baseline was -10.71 (95% CI: -12.90, -8.51, p < 0.001) for IPSS, -2.1 (95% CI: -2.61, -1.58, p < 0.001) for IPSS-QoL, and 2.86 (95% CI: 1.68, 4.04, p < 0.001) for Qmax, corresponding to 49%, 47%, and 27% improvements, respectively. These improvements were sustained through 24 months, with 48%, 55%, and 32% improvement relative to baseline in IPSS, IPSS-QoL, and Qmax, respectively. CONCLUSIONS:At 24-months, treatment with the Spring System resulted in immediate, significant, and durable improvements compared with baseline, supporting its role as a minimally invasive, tissue-preserving treatment option for men with lower urinary tract symptoms secondary to BPH. TRIAL REGISTRATION:NCT03595735, NCT03577236, NCT04309695.
BACKGROUND:Androgen deprivation therapy (ADT) + androgen receptor pathway inhibitor (ARPI) ± docetaxel represent the standard of care in patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, some patients still have early progression (EP). EMETPRO is a multicentric, retrospective registry of patients with EP mHSPC. METHODS:Patients with EP mHSPC were defined as patients who had progression ≤6 months under ADT+docetaxel or ADT + ARPI or ≤9 months from ADT monotherapy start. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS). RESULTS:Data from eligible patients treated between 2005 and 2023 were retrospectively collected. 201 (50%) patients received ADT monotherapy, while 124 (31%) and 76 (19%) received ADT+docetaxel and ADT + ARPI, respectively. 365 (91%) patients underwent first-line treatment for mCRPC-majority of the ADT monotherapy received ARPI (38%) or docetaxel (34%), whereas 69% of the ADT+docetaxel received ARPI and 62% of the ADT + ARPI received docetaxel. In the group of patients treated with ADT the median PFS was 6.8 months while the median OS was 26.4. In the group of patients treated with combination therapy the median PFS and OS was 4.9 and 18.6 months for patients who received docetaxel and 5.6 and 19.5 months for patients who received ARPI, respectively. Neither the first-line mCRPC treatment nor the genetic profiles were associated with survival outcomes. CONCLUSIONS:The results of our study suggest that patients with EP mHSPC are characterized by poor outcomes regardless of the type of treatment received at progression. The optimal first-line mCRPC therapy to use in these patients remains a crucial unmet clinical need.
