Efficacy and safety of darolutamide in combination with androgen deprivation therapy and docetaxel in European patients from the phase 3 ARASENS trial.

Early prediction via PET/CT for skeletal-related events in osteoporotic men with metastatic prostate cancer undergoing androgen deprivation therapy.

PSA Response as a Prognostic Factor of Overall Survival in Patients with Metastatic Hormone-sensitive Prostate Cancer Treated with Apalutamide: Real-world Evidence.

Cumulative dose analysis following elective pelvis re-irradiation at junction with primary prostate radiotherapy from the OLIGOPELVIS GETUG P07 trial.

Silencing fatty acid binding protein 5 inhibits prostaglandin E2 and activates CD8 T cells in castration-resistant prostate cancer.

Metastatic hormone-sensitive prostate cancer (mHSPC) remains clinically heterogeneous despite upfront treatment intensification. The commonly used CHAARTED high-volume and LATITUDE high-risk criteria stratify metastatic burden but do not explicitly incorporate Eastern Cooperative Oncology Group (ECOG) performance status (PS). We developed and internally assessed a simple bedside prognostic score integrating PS with aggressive metastatic burden in a real-world mHSPC cohort. We retrospectively identified consecutive patients with histologically confirmed prostate adenocarcinoma who initiated first-line androgen deprivation therapy (ADT)-based systemic therapy for mHSPC between January 2014 and May 2025. Metastases were assessed primarily by conventional imaging (bone scintigraphy and computed tomography [CT]). The PS-Metastatic Burden score (0-2) assigned 1 point each for ECOG PS ≥ 1 and for aggressive metastatic burden defined as bone scan extent of disease (EOD) ≥ 3 and/or liver metastasis. The primary endpoint was overall survival (OS). Model fit and discrimination were compared with CHAARTED and LATITUDE using Akaike information criterion (AIC) and Harrell's concordance index (C-index) in a common complete-case dataset. Among 886 patients (median follow-up 36.9 months), 218 deaths occurred. Score distribution was 0/1/2 points in 592 (66.8%)/257 (29.0%)/37 (4.2%). OS was clearly separated across groups (log-rank p < 0.001): median OS was not reached for score 0 during follow-up; it was 49.0 months for score 1, and 37.3 months for score 2. In complete cases (n = 869; deaths = 211), hazard ratios versus score 0 were 2.16 (95% confidence interval [CI] 1.62-2.87) for score 1 and 3.08 (95% CI 1.87-5.08) for score 2 (both p < 0.001). The PS-Metastatic Burden score showed superior performance (AIC 2513.2; C-index 0.600) compared with CHAARTED and LATITUDE; adding PS to those frameworks improved performance modestly but remained inferior. Upfront androgen receptor pathway inhibitor (ARPI) use was lower in ECOG PS ≥ 1 than PS 0 (38.4% vs 60.8%; p < 0.001), and best supportive care initiation or death increased stepwise across score groups (21.3%, 37.2%, 51.4%). A two-factor bedside score integrating host reserve and aggressive metastatic burden provides pragmatic prognostic stratification for real-world mHSPC in the upfront ARPI era and offers information beyond CHAARTED/LATITUDE. External validation is warranted.

Unfavorable intermediate-risk prostate cancer (UIR-PCa) represents a biologically heterogeneous subgroup with a higher risk of recurrence compared with favorable intermediate-risk disease. Contemporary management frequently includes dose-escalated radiotherapy (RT) combined with short-term androgen deprivation therapy (ADT). Whether additional intraprostatic dose escalation using a simultaneous integrated boost (SIB) provides incremental oncologic benefit in this setting remains uncertain. We retrospectively analyzed 194 patients with UIR-PCa treated at three institutions between 2010 and 2023. All patients received image-guided intensity-modulated or volumetric modulated arc RT to 78 Gy with short-term ADT. An MRI-guided intraprostatic SIB (up to 86 Gy) was delivered in 77 patients (39.7%) at clinician discretion. Primary endpoints were biochemical recurrence-free survival (bRFS), distant metastasis-free survival (DMFS), and prostate cancer-specific mortality (PCSM). Multivariable Cox and competing-risk regression models were used to assess predictors of outcome. After a median follow-up of 105 months, 8-year bRFS and DMFS rates for the entire cohort were 93.7% and 95.7%, respectively. Addition of SIB was not associated with improved bRFS (93.5% vs 93.6%, p = 0.36), DMFS (94.6% vs 96.7%, p = 0.15), or PCSM. Percent positive biopsy cores ≥ 50% was the only independent predictor of inferior bRFS on multivariable analysis. Treatment-related toxicity was low in both groups, with no significant differences in late grade ≥ 2 gastrointestinal or genitourinary toxicity. In patients with UIR-PCa uniformly treated with dose-escalated, image-guided RT and short-term ADT, long-term oncologic outcomes were excellent. The addition of an intraprostatic SIB was safe but did not confer measurable improvement in biochemical or distant disease control. These findings support a selective rather than routine use of focal intraprostatic dose escalation in contemporary UIR-PCa management.

It is imperative to identify patients with prostate cancer (PCa) who will not benefit from androgen receptor signaling inhibitors and to improve their clinical outcomes. Using artificial intelligence (AI), in this multicenter cohort study of 623 PCa patients, we identified 13 cellular morphometric biomarkers (CMBs), as a New Approach Methodology (NAM), from whole slide images of needle biopsies in clinical trial specimens (NCT02430480, n=37) that accurately predicted response to neoadjuvant androgen deprivation therapy (NADT) plus enzalutamide (AUC: 0.981, 95% CI [0.979, 0.983]). Importantly, the 13-CMB model stratified PCa patients into responders and non-responders after NADT across two independent hospital cohorts. In one cohort (n=122), the model identified groups with significantly different pathologic complete response (pCR) (p=0.0005) and biochemical recurrence-free survival (BCRFS) (p=0.024). In the second cohort (n=60), the model similarly distinguished patients with significantly different BCRFS (p=0.031). The 13-CMB model also stratified PCa patients in the TCGA-PRAD cohort (n=396) with distinct progression-free survival (p=0.0017). Importantly, across hospital cohorts and the TCGA-PRAD cohort, the 13-CMB model demonstrated significant and independent clinical value after adjustment for established clinical factors and commonly used genomic biomarkers, including Decipher and Oncotype DX. Furthermore, CMBs accurately predicted the molecular differences between stratified patient groups and the potential benefit from mTOR inhibitors in non-responders, which were validated through IHC staining and patient-derived organoids (n=8), respectively. Overall, our AI-powered CMB model, relying only on routine needle biopsy specimens, could potentially serve as a robust solution for precision management of PCa patients.

Androgen deprivation therapy (ADT) is the cornerstone of advanced prostate cancer treatment, aiming to achieve castrate testosterone levels. Luteinizing hormone-releasing hormone (LHRH) agonists are widely used, but intrinsic resistance, although rare, may pose significant therapeutic challenges. We report a 75-year-old man with de novo low-volume metastatic prostate cancer who experienced unusual refractoriness to LHRH agonist therapy. Despite correct administration of leuprolide and good treatment adherence, testosterone levels did not drop and instead progressively increased over five months. This occurred concurrently with a marked PSA decline following the addition of the androgen receptor pathway inhibitor (ARPI) apalutamide. Drug-drug interactions, pharmacological interference, and other common causes of treatment resistance were ruled out. Upon switching to the LHRH antagonist degarelix, adequate testosterone suppression was rapidly achieved. This case highlights a rare biochemical failure of LHRH agonist therapy, possibly due to primary resistance or inadequate receptor desensitization. The concomitant use of an ARPI masked ADT failure by suppressing PSA despite elevated testosterone. This case emphasizes the still relevant need for periodic testosterone monitoring to ensure effective hormonal suppression.

Androgen deprivation therapy (ADT) remains the standard of care for the treatment of advanced and metastatic prostate cancer (PC). However, in older patients, the choice of treatment must be made carefully, as they often have comorbidities and are at risk of potential side effects. Newer hormonal therapies (androgen receptor pathway inhibitors, ARPIs) have expanded the treatment spectrum, raising questions about optimal therapy for older patients. This article provides an overview of the evidence-based use of ADT and ARPI in older patients, with aparticular focus on relevant guideline recommendations and study results across different stages of prostate cancer. It also describes how individualized treatment decisions can be made in clinical practice. Selective literature review on ADT and ARPI in older patients. Data from relevant clinical trials, current evidence, and recommendations from international and national guidelines (e.g., EAU, S3) are considered. For metastatic hormone-sensitive prostate cancer (mHSPC), the combination of ADT and ARPI has proven beneficial, particularly for patients with alife expectancy of more than 1year and agood performance status. Network meta-analyses show that dual- and triple-agent therapies improve overall survival in older patients, while side effects increase. The use of ADT + ARPI improves survival rates but requires anuanced assessment of side effects and quality of life, particularly in very old patients. Geriatric assessment helps classify patients into different risk groups and plays acentral role in treatment decisions.

High-grade prostate cancer is usually monitored with prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA)-targeted positron emission tomography-CT (PET/CT). We describe an older man with a history of Gleason 9 prostate adenocarcinoma treated with androgen deprivation therapy, external beam radiotherapy and brachytherapy who later developed haematuria and functional decline. Despite a large invasive pelvic mass, his PSA remained undetectable, and PSMA PET/CT was negative, initially suggesting an alternative diagnosis such as rectal carcinoma. Colonoscopic biopsy was non-diagnostic, but prostate biopsy confirmed recurrent Gleason 9 adenocarcinoma. The patient deteriorated rapidly and died within 3 months. This case underscores the need for histological confirmation when PSA, PSMA PET/CT, and the clinical picture are discordant, even in previously well-controlled disease.

Prostate cancer is well known to be androgen-dependent, with growth directly relying on the androgen receptor signaling pathway. In fact, androgen deprivation therapy, with or without Docetaxel and/or newer hormonal drugs such as Abiraterone acetate, Enzalutamide, Apalutamide, and Darolutamide, remains the most effective systemic treatment for metastatic disease. Beyond PSA detection, there is a lack of standardized biohumoral markers to understand the biology of metastatic castrate-sensitive prostate cancer (mCSPC), predict response to newer therapies such as immunotherapy, and identify a true oligometastatic state. A comprehensive, non-systematic literature review across Scopus, Google Scholar, Medline, EMBASE, and the Cochrane Library was conducted. New evidence was identified, gathered, and screened for relevance, limited to English-language publications. Information and recommendations on the emerging mCSPC biomarkers, their possible integration, and application for care decisions were evaluated. Our work aimed to summarize the current understanding of molecular characterization of mCSPC and the evidence on the role of emerging molecular biomarkers in guiding personalized treatment for mCSPC. The integration of data extracted from imaging with the molecular and genetic profiles of a specific tissue, using artificial intelligence, will help assess the genetic and biochemical makeup of living tissue.

Prostate cancer (PCa) has been identified as the most prevalent form of cancer among males and the third leading cause of death from cancer in the European male population. Early-stage PCa can be treated with prostatectomy and radiotherapy, whereas metastatic cases require androgen deprivation therapy and may benefit from targeted radionuclide therapy (TRT). The objective of our research is to develop and validate an automated production of [177Lu]Lu-PSMA I&T for clinical use. [177Lu]Lu-PSMA I&T is a radioligand therapy (RLT) that targets prostate-specific membrane antigen (PSMA), which is overexpressed in metastatic and castration-resistant prostate cancer. This work delineates the development and validation of analytical methodologies for the automated production of [177Lu]Lu-PSMA I&T with a GAIA-LUNA device from Elysia, in addition to the quality control measures implemented to ensure compliance with Good Manufacturing Practices and the European Pharmacopoeia. Three validation batches were produced, and the investigational medicinal product dossier was submitted to the French National Agency of Medicine and Health Products Safety (ANSM) for authorization. PSMA-I&T was radiolabeled with 177Lu using an automated radiosynthesis device, the GAIA-LUNA, from Elysia. Furthermore, we demonstrated the 72-h stability of the [177Lu]Lu-PSMA I&T preparations at room temperature, a development that facilitates the potential subcontracting of [177Lu]Lu-PSMA I&T production to other medical facilities. The findings of this study underscore the potential of [177Lu]Lu-PSMA I&T as a therapeutic option for patients with metastatic castration-resistant prostate cancer (mCRPC) who have contraindications to chemotherapy or hormonotherapy, and highlight the importance of implementing rigorous quality control measures in the development of radiopharmaceuticals.

With the use of modern imaging technology such as prostate-specific membrane antigen positron emission tomography-computed tomography (PSMA PET-CT), compared to conventional imaging with CT and bone scan, in the primary staging of localized prostate cancer and in the setting of PSA failure after local therapy, an increasing number of men are being diagnosed with metastatic prostate cancer with alow tumor burden. At the same time, the combination of androgen deprivation therapy (ADT) with androgen receptor pathway inhibitors (ARPI) has significantly improved the response rate and prognosis in metastatic hormone-sensitive prostate cancer. As aresult, interest has in recent years grown in optimizing treatment for patients with low tumor burden by reducing treatment intensity. Strategies under evaluation include metastasis-directed therapy (MDT), intermittent systemic therapy and combinations of both. To date, no randomized phase3trials have demonstrated abenefit of either MDT alone or in combination to standard treatment, nor of intermittent strategies in oligometastatic prostate cancer. Nevertheless, experts consider the use of MDT as well as intermittent treatment with ADT + ARPI to be justified in selected cases. For clinical practice, it is important that treatment decisions adhere to the definition of oligometastatic disease (maximum of5 metastases in bone or lymph nodes on PSMA PET-CT) and take into account the biology of the disease (synchronous vs. metachronous). The concepts of MDT and intermittent systemic therapy appear promising and patient participation in ongoing clinical trials is crucial.

Salvage radiotherapy (SRT) is the standard of care for patients with biochemical recurrence (BCR) after radical prostatectomy (RP). Several randomized trials have evaluated the addition of hormonal therapy (HT), including androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs), to SRT; however, differences in patient selection, treatment duration, and endpoints have led to inconsistent results. We performed an updated systematic review and meta-analysis to clarify the clinical benefit of adding HT to SRT in this setting. A comprehensive literature search of PubMed/MEDLINE, EMBASE, the Cochrane Library, ClinicalTrials.gov, and ASCO and ESMO meeting abstracts was conducted through April 2025. Randomized phase II-III trials enrolling patients with confirmed BCR after RP and comparing SRT with or without HT were included. Five trials (GETUG-AFU 16, RTOG 9601, RTOG 0534/SPPORT, RADICALS-HD, and SALV-ENZA), comprising 4536 patients, met the eligibility criteria. Hazard ratios (HRs) and 95% confidence intervals (CIs) for metastasis-free survival (MFS), progression-free survival (PFS), biochemical progression-free survival (bPFS), and overall survival (OS) were pooled using fixed- or random-effects models according to heterogeneity. Analyses were stratified by HT duration (short-term vs. long-term), and subgroup analyses were performed based on pathological features. Short-term HT combined with SRT significantly improved bPFS (HR = 0.57; 95% CI: 0.46-0.71, p < 0.00001), PFS (HR = 0.58; 95% CI: 0.49-0.69; p < 0.00001), and MFS (HR = 0.82; 95% CI: 0.69-0.96; p = 0.02). Long-term HT was also associated with improved MFS (HR = 0.76; 95% CI: 0.61-0.94; p = 0.01). No statistically significant OS benefit was observed with either short-term or long-term HT. Subgroup analyses showed a significant MFS benefit in patients with positive surgical margins (HR = 0.68; 95% CI: 0.47-0.98; p = 0.04), whereas no clear benefit was detected in patients with Gleason score ≥8 or negative margins. The addition of HT to SRT improves disease control outcomes in patients with BCR after RP, particularly in those with positive surgical margins, although no overall survival benefit was demonstrated. These findings support a tailored approach to treatment intensification in the salvage setting.

Bone metastasis is a leading cause of death in prostate cancer (PC) patients. Although androgen-deprivation therapy (ADT) combined with novel androgen-targeted agents constitutes the cornerstone of systemic treatment, its efficacy is limited. We investigated the adrenal contribution in promoting progression of castration-resistant PC (CRPC) within bone using a preclinical intratibial xenograft model (VCaP, 22Rv1, and LNCaP cells). Mice underwent orchiectomy (ORX) to mimic ADT, with or without adrenalectomy (ORX+ADX) to eliminate adrenal contribution. A significant increase in bone mineral density (BMD) was observed in tumor-grafted tibiae in ORX-treated mice compared to controls (p<0.001), indicating a strong tumor-induced sclerotic response. In contrast, ORX+ADX reduced tumor take rate by approximately 50% and decreased tumor-induced BMD by over 80% (p<0.001). Transcriptomic analysis revealed that ADX downregulated tumor-induced transcripts in bone by over 90%, including osteogenic (Lox, Sparcl1, Bmp2, Postn, Col1a1) and pro-angiogenic (Bmper, Pecam-1, Esam) signatures. Additionally, BMP, PI3K/Akt and ERK1/2 signaling pathways were associated with the tumor-induced bone response. Both high serum progesterone and intratumoral levels of dihydrotestosterone (DHT) were associated with the sclerotic bone phenotype. ADX markedly reduced intratumoral DHT and downregulated glycolytic genes (HK2, PFK2, LDHA) and secretory proteins expressed by the tumor, including Stanniocalcin 2, potentially mediating paracrine effects in the sclerotic bone response. Altogether, these findings highlight the critical role of adrenal- dependent androgen synthesis, particularly via progesterone, in driving the sclerotic CRPC in bone. Our findings suggest that a comprehensive blockade of adrenal contribution is essential to prevent the sclerotic bone response associated with CRPC.

Baseline Frailty, Treatment Intensity, and Clinical Outcomes Among Older Adults with Locally-advanced Prostate Cancer.

This podcast will provide an overview of androgen deprivation therapy (ADT) for advanced prostate cancer, including the different treatment options currently available. The podcast will also cover the key results of recently published studies that looked at patient preferences for different characteristics of ADT. Additionally, a physician and patient will each discuss the importance of shared decision-making in selecting the optimal ADT option. They will address key factors to discuss when evaluating ADT options, and emphasize the importance of aligning treatment choices with patients' individual needs and the best available scientific evidence.

The prognosis of newly diagnosed metastatic prostate cancer is highly variable. The primary objective of the PARADIGM prospective cohort study was to evaluate predictors of survival in blood collected at the start of each of the first six treatment cycles from 114 patients with high-volume metastatic prostate cancer (biologically male) who were starting androgen deprivation therapy in combination with docetaxel or an androgen receptor pathway inhibitor. Here circulating tumor DNA (ctDNA) was detected in 29% of patients after 6-12 weeks of combination therapy (compared to 70% before any treatment) and associated with 12 month overall survival of 73% versus 99% for patients who were ctDNA-negative and 24 month survival of 50% versus 85%. The secondary objective was to test ctDNA with serum prostate-specific antigen (PSA). In multivariable models, both were independent risk factors on combination treatment with a hazard ratio of death of 20.34 for the poorest prognosis group, but only ctDNA was associated with shorter survival on androgen deprivation before the start of combination therapy. Using ctDNA with serum PSA and clinical characteristics can improve the accuracy of survival prediction and should be evaluated for ctDNA-informed treatment modification. ClinicalTrials.gov: NCT04067713 .

Circulating microbial metabolites and the gut-prostate axis in prostate cancer: Implications for laboratory biomarkers and therapeutic response.