Prostate cancer (PCa) remains a significant health concern for males, and serum/glucocorticoid-regulated kinase-1 (SGK1) plays a crucial role in its pathogenesis. This provides a promising target for the development of novel therapies against PCa. Herein, we reported the structural optimization of the hit compound H1, which was discovered in our previous work as an SGK1 inhibitor. Based on docking research for the active binding conformation of compound H1, a series of novel 4-trifluoromethyl quinoline derivatives were developed by replacing the 6-methoxy group in the quinoline skeleton of compound H1 with a larger aryl ring to occupy the hinge region of SGK1. Among them, compound 12f showed the strongest SGK1 inhibitory potency, with an IC50 value of 0.39 μM, representing a 7.8-fold improvement over compound H1. Molecular docking studies revealed that the 6-methoxyphenylamine moiety of compound 12f effectively extends into the hinge region of SGK1, establishing a crucial hydrogen bonding interaction with Glu183 that enhances its biological potency. In vivo, compound 12f effectively suppressed tumor growth in the PC3 xenograft model in BALB/c nude mice without inducing any observable toxicity. Moreover, mechanistic studies showed that compound 12f hindered PC3 cell migration and invasion, improved the thermal stability of SGK1 protein in PC3 cells, decreased SGK1 protein levels in tumor tissues, and effectively inhibited the phosphorylation of SGK1 and its substrates in PC3 cells in a dose- and time-dependent manner. In summary, the results of this study highlight the potential of 12f as a lead compound for further optimization in the development of new therapies against PCa targeting SGK1.

Enzalutamide (ENZ) and Abiraterone Acetate (AA) are both first-line treatments for castration-resistant prostate cancer (CRPC). CRPC patients may switch from ENZ to AA or from AA to ENZ, if they do not respond well to the treatment, or experience intolerable side effects. This study examine treatment switching from ENZ to AA or from AA to ENZ, while investigating death as a competing risk. Whether ENZ compared to AA was associated with a longer time to starting oral opioids was also investigated.

An active comparator new-user design was used to identify 1406 men diagnosed with CRPC who received ENZ and AA using the Surveillance, Epidemiology, and End Results-Medicare Linked Database from 2012 to 2016. Inverse probability treatment weights (IPTW)-adjusted Fine-Gray competing risk models were used to compare the switching drugs and time-to-first use of oral opioids after initiating ENZ and AA.

Most patients (61 %) received AA, while 39 % received ENZ. Overall, ENZ demonstrated a significant reduction in the Sub-distribution Hazard Ratio (SHR) for switching treatment (IPTW-adjusted SHR 0.63; 95 % CI, 0.54-0.73; P < 0.001), indicating a decrease in treatment switching compared to AA. Cumulative incidence curves revealed substantial differences in switching patterns over time (Gray's test, p < 0.001). For time-to-first oral opioid use, the IPTW-adjusted SHR when comparing ENZ to AA was 0.95 (95 % CI, 0.83-1.09; P = 0.48), showing no significant difference between the two groups.

Patients who began their treatment with ENZ exhibited a substantially lower hazard of switching to AA when compared to those who started with AA.

Olaparib exhibits antitumor effects in castration-resistant prostate cancer patients with germline mutations in DNA repair genes. We previously reported that simvastatin reduced the expression of DNA repair genes in PC-3 cells. The efficacy of combination therapy using olaparib and simvastatin as "BRCAness" in castration-resistant and taxane-resistant prostate cancers was evaluated in this study.

PC-3, LNCaP, and 22Rv1 human prostate cancer cell lines were used to develop androgen-independent LNCaP cells (LNCaP-LA). mRNA and protein expression levels were evaluated by quantitative real-time polymerase chain reaction and western blot analysis, respectively. Cell viability was determined using the MTS assay and cell counts. All evaluations were performed on cells treated with simvastatin with or without olaparib.

The mRNA levels of BRCA1, BRCA2, RAD51, FANCD2, FANCG, FANCA, BARD1, RFC3, RFC4, and RFC5, which are known DNA repair genes, were downregulated by simvastatin in androgen-independent prostate cancer cells, such as PC-3, LNCaP-LA, and 22Rv1 cells. In contrast, the expression of all these genes remained unchanged in androgen-dependent LNCaP cells following treatment with simvastatin. Furthermore, simvastatin increased the expression of above stated genes in normal prostate stromal cells (PrSC). The reduction in BRCA1 and BRCA2 expression following siRNA transfection increased the cytocidal effects of Olaparib in PC-3 and LNCaP-LA cells. The combination of olaparib and simvastatin further inhibited cell proliferation compared to monotherapy with either drug in PC-3, 22Rv1, and LNCaP-LA cells but not in PrSC cells. In a 22Rv1-derived mouse xenograft model, the combination of olaparib and simvastatin enhanced the inhibition of cell proliferation. Moreover, we established a 22Rv1 cell line with acquired resistance to Cabazitaxel (22Rv1-CR). In 22Rv1-CR cells, simvastatin also decreased the expression of BRCA1, BRCA2, and FANCA, and the combination of olaparib and simvastatin further enhanced the inhibition of cell proliferation compared with treatment with either of the drugs alone.

Simvastatin altered the expression of several genes associated with DNA repair in castration-resistant and taxane-resistant prostate cancer cells. The combination of poly (ADP-ribose) polymerase inhibitors and drugs that decrease DNA repair gene expression can potentially affect castration-resistant and taxane-resistant prostate cancer growth.

Prostate cancer represents a significant oncological challenge, with its natural history predominantly driven by androgen receptor (AR) signaling. The pivotal role of this pathway underscores the rationale for targeting AR activity in therapeutic strategies. However, the development of resistance mechanisms has highlighted the need for advanced therapies to address the complexity of the castration-resistant status.

We analyzed the evolving role of second-generation androgen receptor signaling inhibitors (ARSIs) in the management of non-metastatic and metastatic castration-resistant prostate cancer, we critically examine emerging combination strategies involving ARSIs, novel agents targeting resistance pathways, and the mechanisms underlying treatment resistance. The review also provides insights into future directions for enhancing outcomes. PubMed literature research using keywords related to castration-resistant prostate cancer and its treatments was performed, including the most relevant trials and reviews.

ARSIs have revolutionized the management of prostate cancer, providing substantial clinical benefits and representing the cornerstone of current treatment paradigms. However, key challenges remain, including determining optimal treatment sequencing, overcoming resistance mechanisms, and tailoring therapies to specific molecular subtypes. Biomarker-driven approaches are critical for refining patient selection and improving therapeutic outcomes. Ongoing trials investigating novel hormonal-axis-directed agents and innovative combination therapies aim to expand the arsenal of effective treatment.

Vaccinia-related kinase 1 (VRK1) is a serine-threonine kinase involved in the proliferation and migration of various cancer cells. However, its role in prostate cancer (PCa), particularly in the development of therapeutic resistance, remains unclear.

We established an androgen-independent PCa cell line derived from LNCaP prostate cancer cells and conducted transcriptome and proteome sequencing together with bioinformatic analyses of large clinical sample databases to investigate the potential role of VRK1 in PCa progression. The correlation between VRK1 and androgen receptor (AR) signaling was evaluated under simulated clinical treatment conditions. The effects of VRK1 on cell proliferation were assessed in vitro and in vivo using Cell Counting Kit-8 and colony formation assays. Additionally, proteome and transcriptome sequencing, combined with rescue experiments were performed to explore VRK1-regulated signaling pathways related to cell proliferation and therapeutic resistance.

VRK1 expression was elevated during the progression of androgen-dependent prostate cancer to castration-resistant prostate cancer under therapeutic conditions, and high VRK1 expression was associated with a poor prognosis in patients with PCa. VRK1 was regulated by AR signaling, and its silencing suppressed PCa cell proliferation both in vitro and in vivo. VRK1 drove cell proliferation and therapeutic resistance in PCa by modulating yes-associated protein 1 (YAP1).

VRK1 serves as a prognostic marker in PCa, regulated by AR signaling. VRK1 depletion inhibited cell proliferation both in vitro and in vivo, while elevated VRK1 upregulated YAP1, promoting cell proliferation and therapeutic resistance.

Corticosteroids are active in castration-resistant prostate cancer (CRPC) by suppression of adrenal androgen production. Triamcinolone is an intramuscular steroid injection which has putative advantages over commonly used steroids, such as dexamethasone and prednisolone.

This was a multicentre, phase II study of intramuscular triamcinolone administered monthly in patients with chemotherapy-naïve CRPC. 55 patients were recruited from 2012 to 2016. Imaging was performed every 3 months. The primary end point was radiological and symptomatic progression-free survival (PFS). Secondary end points included PSA progression, weight changes, and toxicity. We also conducted an exploratory analysis on steroid androgenic precursors, collected before and 1 month after triamcinolone, to measure correlation to PFS.

At a median follow-up time of 18.7 months, the median radiological PFS was 9.4 months (95% confidence interval [CI]: 7.4-20.3 months), and the 6-month radiological PFS rate was 69.1% (95% CI: 55.1%-79.5%). The 50% PSA response rate was 63.6% (95% CI: 49.6-76.2). There were no treatment-related deaths. The most common grade 3 toxicity was hypertension (44%), but only five patients (9%) required concomitant medication. Proximal myopathy was observed in 22 patients (40%). There was no evidence of weight gain (mean weight 83.5 kg pre-study and 79.8 kg post-study). Urinary total androgen metabolites and dehydroepiandrosterone did not predict response to triamcinolone.

Intramuscular triamcinolone is an effective hormonal agent in CRPC. Its side-effect profile is different from other steroids and has the advantage of supervised administration.

The treatment of metastatic castration-resistant prostate cancer (mCRPC) has been rapidly evolving over the last two decades. The advent of new androgen receptor pathway inhibitors (ARPIs) such as abiraterone acetate or enzalutamide marks a great advance for treating mCRPC patientd in the pre- and post-docetaxel settings. The subsequent approval of ARPIs in early stages-i.e., metastatic hormone-sensitive (mHSPC) or nonmetastatic CRPC-led to a realignment of subsequent treatment choices upon progression to mCRPC, given the possibility of cross-resistance between ARPIs. Therapies with mechanisms of action different from those of ARPIs are now the focus of new treatment developments. Also, this anomalous situation brings the focus back to well-known treatments currently used later in the treatment sequence. This is the case of radium-223 which, when administered with enzalutamide, has recently been shown to prolong radiographic progression-free survival vs. enzalutamide alone in the first line in asymptomatic or mildly symptomatic patients with no known visceral metastases. In this narrative review, we summarize the treatment landscape for mCRPC, both from a historical and practical point of view, to understand the new potential of radium-223 as a treatment option in this setting.

Abiraterone and enzalutamide are both approved in the United States for the treatment of metastatic castration-resistant prostate cancer (mCRPC). The objective of this study was to compare the real-world effectiveness and cardiovascular safety of these agents, drawing from a cohort of older adult patients diagnosed with mCRPC.

The Surveillance, Epidemiology, and End Results-Medicare database was used to conduct an observational study comparing three-year overall survival and one-year risk of major adverse cardiovascular events (MACE) between initiators of abiraterone or enzalutamide between September 2012 and June 2017. Inverse-probability-of-treatment weighting was used to balance measured confounders. MACE was defined as a hospitalization for myocardial infarction, heart failure, or ischemic event (stroke or transient attack). Results were additionally stratified by levels of a claims frailty index (robust, prefrail, frail) and the presence of baseline cardiovascular comorbidities.

The study population consisted of 4622 male adults 66 years of age and older diagnosed with mCRPC, of which 2430 initiated abiraterone and 2192 enzalutamide. The adjusted three-year overall survival was lower in patients initiating abiraterone (27.9 %) than enzalutamide (31.5 %) (adjusted survival difference [aSD] = -3.6 %, 95 % CI: -6.2 %, -0.9 %). In frailty-stratified analysis, no survival difference was found for the robust (aSD = 0.6 %, 95 % CI: -5.0 %, 6.3 %) or frail (aSD = -1.2 %, 95 % CI: -6.1 %, 3.7 %) subgroups, but there was lower survival with abiraterone for the prefrail group (aSD = -5.9 %, 95 % CI: -9.6, -2.3). The adjusted one-year risk of MACE was higher in abiraterone initiators (5.5 %) than enzalutamide initiators (3.6 %) (adjusted risk difference [aRD] = 1.8 %, 95 % CI: 0.6 %, 3.1 %); the increase was significant in the frail (aRD = 4.8 %, 95 % CI = 1.4 %, 8.3 %) and pre-frail subgroups (aRD =1.9 %, 95 % CI: 0.1 %, 3.6 %) but not the robust subgroup (aRD = -0.3 %, 95 % CI: -1.8 %, 1.2 %).

The three-year survival of abiraterone initiators was slightly lower than that of enzalutamide initiators, though the agents showed similar survival for patients with robust fitness. A one-year increase in MACE risk was observed in abiraterone initiators, especially amongst frail individuals, highlighting the importance of assessing frailty during therapy selection.

Interim analysis of the ENZA-p trial showed improved prostate-specific antigen (PSA) progression-free survival with the addition of lutetium-177 [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 to enzalutamide as first-line treatment of metastatic castration-resistant prostate cancer. Here, we report the secondary endpoints of overall survival and health-related quality of life (HRQOL) with longer follow-up.

ENZA-p was a multicentre, open-label, randomised, phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older who had not previously been treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [68Ga]Ga PSMA-PET-CT-positive disease, an Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for study site, disease burden, early docetaxel, and previous treatment with abiraterone. Treatment was oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq [177Lu]Lu-PSMA-617 every 6-8 weeks. The primary endpoint was prostate-specific antigen (PSA) progression-free survival, which has been previously reported. Overall survival, defined as the interval from the date of randomisation to date of death from any cause, or the date last known alive, and HRQOL were key secondary endpoints. HRQOL was assessed with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and the Patient Disease and Treatment Assessment Form. For HRQOL analyses, deterioration-free survival was measured from randomisation until the earliest occurrence of death, clinical progression, discontinuation of study treatment; or a worsening of 10 points or more from baseline in physical function, or in overall health and QOL. Analyses of these secondary endpoints were prespecified and are by intention to treat. The trial is registered with ClinicalTrials.gov, NCT04419402, and follow-up is complete.

Between Aug 17, 2020, and July 26, 2022, 79 patients were randomly assigned to enzalutamide and 83 to enzalutamide plus [177Lu]Lu-PSMA-617. 96 deaths was reported after a median follow-up of 34 months (IQR 29-39): 53 (67%) in the enzalutamide group and 43 (52%) in the enzalutamide plus [177Lu]Lu-PSMA-617 group. Overall survival was longer in the enzalutamide plus [177Lu]Lu-PSMA-617 group than the enzalutamide group (median 34 months [95% CI 30-37] vs 26 months [23-31]; HR 0·55 [95% CI 0·36-0·84], log-rank p=0·0053). HRQOL was rated by 154 (95%) of 162 participants. Deterioration-free survival at 12 months and stratified log-rank p values favoured enzalutamide plus [177Lu]Lu-PSMA-617 for both physical function (median 10·64 months [95% CI 7·66-12·42] vs 3·42 months [3·19-7·89]; HR 0·51 [95% CI 0·36-0·72], log-rank p<0·0001) and overall health and QOL (8·71 months [6·41-11·56] vs 3·32 months [3·09-5·26]; HR 0·47 [95% CI 0·33-0·67], log-rank p=0·0001). Mean scores for pain until progression favoured enzalutamide plus [177Lu]Lu-PSMA-617 over enzalutamide (difference 7·3 [95% CI 1·6-12·9]; p=0·012). Mean scores for fatigue until progression favoured enzalutamide plus [177Lu]Lu-PSMA-617 over enzalutamide (difference 5·9 [95% CI 1·1-10·7]; p=0·016). The frequency of self-rated xerostomia was lower in the enzalutamide group than in the enzalutamide plus [177Lu]Lu-PSMA-617 group (43 [57%] of 75 vs 58 [74%] of 78; p=0·039), and scores were not significantly different between groups for all other domains. Grade 3-5 adverse events occurred in 35 (44%) of 79 patients in the enzalutamide group and 37 (46%) of 81 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group. No deaths were attributed to study treatment in either group.

The addition of [177Lu] Lu-PSMA-617 to enzalutamide was associated with improved survival and some aspects of HRQOL in patients with high-risk metastatic castration-resistant prostate cancer. Our findings warrant phase 3 evaluation of adaptive-dosed [177Lu] Lu-PSMA-617 in combination with androgen receptor pathway inhibitors in people with metastatic prostate cancer.

The Prostate Cancer Research Alliance initiative (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, RoyMorgan, AdAcAp (a Novartis company), and Astellas.

There is no cross-sectional comparison on therapeutic and adverse effects for treatments of metastatic castration-resistant prostate cancer (mCRPCa). We aimed to horizontally compare them for all common first-line and second-line therapies.

We conducted a network meta-analysis with a systematic review in four databases (Pubmed, Web of Science, Embase, and Cochrane Library) up to January 5th, 2025. All randomized controlled trials (RCT) related to mCRPCa treatments with a clear description in study design were included. Endpoints included the radiographic progression-free survival (rPFS), overall survival (OS), time to PSA progression (TTPP), PSA progression rate (PSARR), and adverse events. All data was extracted by two researchers and analyzed with Gemtc package in R and Stata15. This NMA protocol was registered online (ID: CRD42025633178).

After screening among 33,694 articles, 24 RCTs involving 13,059 cases were included. For first-line treatments, combination therapies with second-generation androgen receptor inhibitors (ARIs) showed superior efficacies in OS [HR of poly(ADP-ribose) polymerase inhibitors (PARPi) + ARI: 0.63 (0.32,1.25)], TTPP [HR of Lu177 + ARI: 0.07 (0.01,0.87)] and PSARR [RR of Lu177 + ARI: 33.02 (15.56,71.62)] with the highest SUCRA (Surface under the Cumulative Ranking Curve) (72%, 91% and 97% respectively). PARPi + ARI also performed best for rPFS (SUCRA: 85%, with an insignificant HR [0.12 (0.02,2.35)]. For post-docetaxel second-line treatments, ARI also emerged as the preferred option. Efficacies of post-ARI second-line treatments were not evaluated due to the lack of related RCTs. No obvious heterogeneity and publication bias was detected during the therapeutic comparison.

This study provided comparative evidence for first-line and post-chemotherapy second-line mCRPCa treatment options. Second-generation ARIs exhibited good efficacy, particularly when combined with other treatments. However, the safety analysis necessitated balance between benefits and adverse events, especially for combination therapies. Stronger evidence is needed through direct comparisons in future clinical trials.

The study was supported by The National Natural Science Foundation of China (No. 82172568).

Androgens play an important role in prostate cancer development and progression. Androgen action is mediated through the androgen receptor (AR), a ligand-dependent DNA-binding transcription factor. AR is arguably the most important target for prostate cancer treatment. Current USA Food and Drug Administration (FDA)-approved AR inhibitors target the ligand-binding domain (LBD) and have exhibited efficacy in prostate cancer patients, particularly when used in combination with androgen deprivation therapy. Unfortunately, patients treated with the currently approved AR-targeting agents develop resistance and relapse with castration-resistant prostate cancer (CRPC). The major mechanism leading to CRPC involves reactivation of AR signaling mainly through AR gene amplification, mutation, and/or splice variants. To effectively inhibit the reactivated AR signaling, new approaches to target AR are being actively explored. These new approaches include novel small molecule inhibitors targeting various domains of AR and agents that can degrade AR. The present review provides a summary of the existing FDA-approved AR antagonists and the current development of some of the AR targeting agents.

Long-acting triptorelin (LAT) (22.5 mg) is a gonadotropin-releasing hormone (GnRH) agonist used in men with prostate cancer. This study investigated the prescription pattern of LAT in a real-world setting and its efficacy.

This was a retrospective review of patients in a tertiary center who were prescribed LAT for prostate cancer from January 2018 to March 2023 after the introduction of LAT in the territory. Demographic data were collected, and LAT prescription patterns were reviewed. These patterns included the indication and duration of prescription, testosterone suppression and characteristics of the primary prostate cancer.

A total of 237 prostate cancer patients were prescribed LAT in the study period. The indications for LAT included metastatic prostate cancer (50.6%), neoadjuvant/adjuvant therapy for radiotherapy (28.7%) and neoadjuvant therapy for radical prostatectomy (5.1%). Among the cohort, 41.4% of the patients were receiving short-acting triptorelin (11.25 mg) before LAT initiation, 15.2% were receiving other GnRH agonists, and 15.6% were receiving GnRH antagonists. The median age at the first dose of LAT and the median treatment duration were 72 (53-94) years and 30 (6-72) months, respectively. During the study period, 92.0% of the patients did not receive another form of hormonal treatment other than LAT. A total of 121 (51.1%) patients had their testosterone level checked after LAT initiation. The median time interval of testosterone measurement after LAT initiation was 8 (1-47) months, with 98.3% of the patients having a testosterone level < 1.7 nmol/L and 92.6% having a level < 0.7 nmol/L. Among the cohort, 1 patient stopped LAT due to hot flashes and muscle weakness.

The LAT adherence rate was high in the setting of hormonal treatment for prostate cancer. Testosterone suppression was satisfactory after the initiation of LAT and was generally well tolerated.

Despite significant progress, prostate cancer remains a leading cause of death. Cyclin-dependent kinase (CDK) 4/6 inhibitors, which are already approved for the treatment of hormone receptor-positive breast cancer, are undergoing extensive testing as monotherapy and in various combinations as a potentially valuable treatment modality in prostate cancer patients. Thus far, a limited number of these studies have published results, which have been largely disappointing.

In this review, we describe the biologic rationale for the use of CDK4/6 inhibitors in prostate cancer, the existing clinical data describing their use in prostate cancer, and ongoing clinical trials of CDK4/6 inhibitors as monotherapy and in combination for the treatment of prostate cancer. In particular, we focus on possible resistance mechanisms that may be particularly relevant in prostate cancer patients, leading to de novo and acquired resistance, and we highlight novel strategies that can overcome this resistance.

Current clinical trials are actively working to (1) refine the role of CDK4/6 inhibitors in prostate cancer patients; (2) develop new inhibitors of other cell-cycle targets, such as CDK2 and CDK7; and (3) explore novel combination therapies with inhibitors of other relevant pathways, such as PI3K or MAPK. Further genomic subtyping of advanced prostate cancer will likely shed light on the subsets of patients most likely to benefit from cell-cycle-targeted agents.

Treatment for metastatic castration-resistant prostate cancer (mCRPC) includes chemotherapy and inhibition of the androgen receptor pathway. However, the optimal treatment sequence in this scenario is not yet fully understood. Therefore, we conducted a systematic review and meta-analysis comparing cabazitaxel versus abiraterone or enzalutamide for efficacy and safety outcomes as second-line therapy in mCRPC patients after docetaxel failure.

We searched PubMed, Embase, and Cochrane databases for interventional studies comparing cabazitaxel versus abiraterone or enzalutamide for patients with mCRPC who have experienced treatment failure with docetaxel as their first-line therapy. We computed hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs).

Eight studies, comprising 1,897 patients were included, of whom 548 (28.8%) received cabazitaxel. Mean follow-up time ranged from 3 to 16.4 months. Median age ranged from 68.1 to 73.9 years in the cabazitaxel group, and 68.0 to 73.1 years in the abiraterone or enzalutamide group. In our meta-analysis, cabazitaxel significantly improved progression-free survival (PFS) rates (HR 0.60; 95% CI 0.47-0.78; p < 0.001) compared to abiraterone or enzalutamide. There were no differences between groups in overall survival (HR 0.76; 95% CI 0.46-1.24; p = 0.27), therapy-related grade ≥ 3 adverse events (AEs) (OR 3.00; 95% CI 0.72-12.40; p = 0.12), and PSA decline ≥ 50% (OR 1.20; 95% CI 0.51-2.80; p = 0.67).

In this systematic review and meta-analysis of men with mCRPC after docetaxel failure, second-line therapy with cabazitaxel was associated with a longer PFS compared with abiraterone or enzalutamide, though without a significant difference in OS.

Rationale: Metastatic prostate cancer in the castration-resistant (mCRPC) setting remains challenging to treat. Prostate-specific membrane antigen (PSMA)-targeted alpha therapy (TAT) is emerging as a promising option. We aimed to systematically review the efficacy and safety of PSMA-TAT in patients with prostate cancer. Methods: A comprehensive search of PubMed/MEDLINE and EMBASE databases was conducted up to October 2024, adhering to the PRISMA guidelines. Selected studies were original research articles evaluating the efficacy and/or safety of PSMA-TAT including at least 10 patients. The outcomes measured included any prostate-specific antigen (PSA) response, ≥50% PSA reduction (PSA50), progression-free survival (PFS), overall survival (OS), and adverse events. PSA50 was pooled using a random-effects model, incorporating individual patient data on PSA50 and previous lines of treatment. Results: Eighteen studies involving 1,155 patients met the inclusion criteria. The majority included heavily pre-treated patients. The most commonly employed radiopharmaceutical was [225Ac]Ac-PSMA-617, in 15 studies. The pooled PSA50 response rate was 65% [95% Confidence interval (CI), 57-72%] with a moderate level of heterogeneity (I² = 81.17%, p < 0.001). Pooled response rates in patients who received none, one, and more than one prior line of treatment were 82% (95% CI, 73-90%), 72% (95% CI, 56-85%), and 55% (95% CI, 48-63%), respectively. PFS varied from 3 to 15 months, and OS from 8 to 31 months. Adverse events were predominantly mild (grades 1-2); severe adverse events (≥ grade 3) included anaemia (11%) and thrombocytopenia (6%). Conclusion: PSMA-TAT holds promising efficacy and an acceptable safety profile for treating metastatic prostate cancer. Randomised controlled trials are needed to optimise treatment protocols toward the implementation of PSMA-TAT into clinical practice.

This exploratory analysis of the CHART trial (ClinicalTrials.gov: NCT03520478) investigated prostate-specific antigen (PSA) kinetics and the correlation between PSA and survival outcomes in high-volume, metastatic, hormone-sensitive prostate cancer (mHSPC).

A total of 654 patients were randomized 1:1 to receive either rezvilutamide plus androgen deprivation therapy (ADT; n = 326) or bicalutamide plus ADT (n = 328). PSA kinetics were evaluated, and the correlation between survival and the achievement of undetectable PSA (≤0.2 ng/mL) or ≥90% PSA reduction (PSA90) was assessed.

The rezvilutamide group exhibited higher proportions of ≥50% PSA reduction (PSA50; 98.2% vs. 87.5%), PSA90 (88.7% vs. 63.1%), and undetectable PSA (38.3% vs. 17.7%) responses compared to the bicalutamide group by 3 months. The rezvilutamide group demonstrated superior efficacy in delaying PSA progression compared to the bicalutamide group (hazard ratio [HR] 0.21, 95% confidence interval 0.16-0.27). The achievement of undetectable PSA and PSA90 by 6 months in the rezvilutamide group was associated with prolonged overall survival (undetectable PSA, HR = 0.34; PSA90, HR = 0.22), radiographic progression-free survival (HR = 0.36, HR = 0.26), time to PSA progression (HR = 0.25, HR = 0.17), and time to castration resistance (HR = 0.34, HR = 0.23) compared to those who did not achieve these PSA milestones. Stratification by baseline PSA level revealed consistent survival improvements with rezvilutamide plus ADT across quartiles.

PSA kinetics is a valuable prognostic factor in mHSPC treated with rezvilutamide plus ADT, and the achievement of undetectable PSA and PSA90 is associated with improved survival. These findings highlight the importance of monitoring PSA kinetics in the management of mHSPC.

This study was funded by Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Androgen-receptor pathway inhibitors such as abiraterone and enzalutamide have demonstrated clinical benefit in patients with metastatic castration-resistant prostate cancer (mCRPC). The aim of this study was to conduct a meta-analysis of published real-world evidence studies comparing outcomes among patients treated with enzalutamide or abiraterone in the first-line setting.

We conducted a systematic literature review to identify eligible studies. Evaluated outcomes were: overall survival (OS), progression-free survival, prostate-specific antigen (PSA) progression-free survival, PSA response, all-grade adverse events, grade ≥3 adverse events, treatment discontinuation, and dose reduction. Each outcome's suitability for meta-analysis was evaluated by assessing whether there were sufficient data to make comparisons between studies, consistency between outcome definitions, and whether the studies adjusted for baseline patient characteristics. Outcomes deemed suitable for meta-analysis were analyzed using fixed-effect and random-effect models to obtain pooled-effect sizes. Sensitivity analyses were conducted to evaluate the robustness of conclusions.

Of 1849 records reviewed, 30 were eligible for inclusion. Most outcomes were deemed unsuitable for meta-analysis due to a lack of adjustment for baseline characteristics, issues with inconsistent outcome definitions, and the small number of studies reporting each outcome. The only outcome deemed suitable for meta-analysis was OS. A total of 17 studies reported hazard ratios (HRs) for OS, 11 of which were adjusted for baseline characteristics. Among the studies reporting adjusted HRs, the pooled-effect estimate favored enzalutamide over abiraterone (reference group) in the fixed-effect model (HR: 0.90 [95% CI: 0.87-0.93]) and the random-effect model (HR: 0.90 [95% CI: 0.86-0.94]). These results were consistent across all sensitivity analyses.

Across all analyses, enzalutamide demonstrated a statistically significant improvement in OS compared with abiraterone. These findings highlight the value of real-world evidence studies to demonstrate the potential of different therapies under real-world conditions and over long periods of time.

Enzalutamide is a potent second-generation antiandrogen commonly used to treat hormone-sensitive and castration-resistant prostate cancer (CRPC) patients. While initially effective, the disease almost always develops resistance. Given that many enzalutamide-resistant tumors lack specific somatic mutations, there is strong evidence that epigenetic factors can cause enzalutamide resistance. To explore how resistance arises, we systematically test all epigenetic modifiers in several models of castration-resistant and enzalutamide-resistant prostate cancer with a custom epigenetic CRISPR library. From this, we identify and validate SMARCC2, a core component of the SWI/SNF complex, that is selectivity essential in enzalutamide-resistant models. We show that the chromatin occupancy of SMARCC2 and BRG1 is expanded in enzalutamide resistance at regions that overlap with CRPC-associated transcription factors that are accessible in CRPC clinical samples. Overall, our study reveals a regulatory role for SMARCC2 in enzalutamide-resistant prostate cancer and supports the feasibility of targeting the SWI/SNF complex in late-stage PCa.

20% of prostate cancer (PC) patients harbor germinal or somatic alterations in homologous recombination repair (HRR) genes, including BRCA1/2. BRCA mutations represent predictive biomarkers for treatment with polyadenosine diphosphate-ribose inhibitors (PARPi). Olaparib has shown efficacy in metastatic castration-resistant PC (mCRPC) and is currently approved in Italy for mCRPC with BRCA1/2 mutations. National and international guidelines strongly recommend BRCA testing in PC. However, genetic testing presents challenges in clinical practice that may limit access to PARPi.

we conducted a survey directed towards members of the Italian Association of Medical Oncology to highlight the level of implementation of national recommendations and issues associated with genetic testing. Through an anonymous questionnaire, the survey collected clinical data of PC patients undergoing BRCA testing and the main difficulties to face in conducting the analysis.

The survey was completed by 108 participants (5% of AIOM members). 52.8% of respondents test BRCA in all metastatic PC patients. If tissue analysis is invalid, only 17% use liquid biopsy, and 15.7% always consider a re-biopsy of a metastatic lesion. A quarter of respondents have to outsource genetic testing to another center and 17.6% have a split process between different institutions. Long timelines, lack of a predefined procedure, and unavailability of liquid biopsy represent the main issues based on respondents' opinions.

BRCA testing in PC still presents several difficulties in clinical practice that can limit access to PARPi treatment. Better implementation of molecular testing to identify BRCA-mutated patients is crucial for tailored treatment in mCRPC.

Cabazitaxel is an effective treatment in metastatic castration-resistant prostate cancer (mCRPC) patients previously exposed to docetaxel and novel hormonal treatments. Understanding the molecular biology of mCRPC disease and taking into account the several approved treatment options, biomarkers are needed to guide decision making including cabazitaxel treatment.

Cababone was a phase II translational study that attempted to identify predictors of cabazitaxel efficacy. mCRPC with documented bone metastases were enrolled prospectively and treated with cabazitaxel 25mg/m2 every 3 weeks. Prostate cancer biopsies, bone marrow aspirates and blood samples were collected for translational research.

Sixty patients were enrolled and 59 received treatment according to protocol. Six-month progression free survival (PFS) rate was 47% (95% CI: 33% - 59%) and 12-month Overall Survival (OS) rate was 70% (95% CI: 56% - 80%). Patients with reactive hematopoiesis had improved PFS and OS with cabazitaxel treatment. Mutations in HRR genes were detected in 7 patients.

No differences in cabazitaxel efficacy were noted according to mutational status of HRR genes analyzed. No new safety issues were detected. In conclusion, CabaBone confirmed efficacy of cabazitaxel in mCRPC patients including the subgroup of patients with HRR mutations. Reactive hematopoiesis in bone marrow biopsies was related to improved survival warranting further investigation of bone biomarkers as predictors of cabazitaxel efficacy.

This study aimed to evaluate the efficacy of androgen receptor signaling inhibitors (ARSIs) combined with androgen deprivation therapy (ADT) for treating castration-sensitive metastatic prostate cancer in Japanese patients, focusing on the effects on time to the development of castration-resistant prostate cancer (CRPC) and overall survival (OS).

This retrospective muti-institutional analysis included 332 patients diagnosed with metastatic prostate cancer in Japan between 2018 and 2023. The patients were categorized into two groups: patients receiving ADT combined with ARSI (ARSI group) and those receiving ADT alone or with bicalutamide (ADT group). Data on demographics, treatments, and outcomes were compared using the Kaplan-Meier method with propensity score matching.

We found an increasing trend in ARSI use over time. The median time to CRPC was significantly longer in the ARSI group than in the ADT group (47.1 vs. 15.2 months, p < 0.001); however, no significant differences in OS were observed before or after propensity score matching. The 1-year-survival rate of patients in the ARSI group tended to be higher than that of patients in the ADT group in subgroups with high tumor volume (96.1% vs. 85.0%) and high Gleason grade (98.1% vs. 85.9%).

Adding ARSI to ADT extended the time to CRPC but did not significantly affect OS. However, it potentially suppressed the short-term risk of death in high-risk subgroups. This study highlights the need for further research to explore the characteristics of Japanese patients with metastatic prostate cancer in whom upfront ARSIs are effective.

The PRESIDE (NCT02288247) randomized trial demonstrated prolonged progression-free survival (PFS) with continuing enzalutamide beyond progression in metastatic castration-resistant prostate cancer (mCRPC) patients starting docetaxel. This study aims to test the associations of PFS and circulating tumor DNA (ctDNA) prior to and after one cycle (cycle 2 day 1 [C2D1]) of docetaxel and with a liquid biopsy resistance biomarker (LBRB; plasma androgen receptor [AR] gain and/or circulating tumor cells [CTCs] expressing AR splice variant 7 [CTC-AR-V7]) prior to continuation of enzalutamide/placebo.

Patients consenting to the biomarker substudy and donating blood before starting docetaxel with enzalutamide/placebo (N = 157) were included. Sequential plasma DNA samples were characterized with a prostate-cancer bespoke next-generation-sequencing capture panel (PCF_SELECT), and CTCs were assessed for AR-V7 (Epic Sciences, San Diego, CA, USA). Cox models, Kaplan-Meier, and restricted mean survival time (RMST) at 18 mo were calculated.

There was a significant association of worse PFS with pre-docetaxel ctDNA detection (N = 86 (55%), 8.1 vs 10.8 mo hazard ratio [HR] = 1.78, p = 0.004) or persistence/rise of ctDNA at C2D1 (N = 35/134, 5.5 vs 10.9 mo, HR = 1.95, 95% confidence interval [CI] = 1.15-3.30, p = 0.019). LBRB-positive patients (N = 62) had no benefit from continuing enzalutamide with docetaxel (HR = 0.78, 95% CI = 0.41-1.48, p = 0.44; RMST: 7.9 vs 7.1 mo, p = 0.50). Conversely, resistance biomarker-negative patients (N = 87) had significantly prolonged PFS (HR = 0.49, 95% CI = 0.29-0.82, p = 0.006; RMST: 11.5 vs 8.9 mo, p = 0.005). Eight patients were unevaluable. An exploratory analysis identified increased copy-number gains (CDK6/CDK4) at progression on docetaxel. Limitations included relatively low detection of CTC-AR-V7. Validation of impact on overall survival is required.

Liquid biopsy gives an early indication of docetaxel futility, could guide patient selection for continuing enzalutamide, and identifies cell cycle gene alterations as a potential cause of docetaxel resistance in mCRPC.

In the PRESIDE biomarker study, we found that detecting circulating tumor DNA in plasma after starting treatment with docetaxel (chemotherapy) for metastatic prostate cancer resistant to androgen deprivation therapy can predict early how long patients will take to respond to treatment. Patients negative for a liquid biopsy resistance biomarker (based on the status of androgen receptor (AR) gene and AR splice variant 7 in circulating tumor cells) benefit from continuing enzalutamide in combination with docetaxel, while patients positive for the resistance biomarker did not. Additionally, we identified alterations in the cell cycle genes CDK6 and CDK4 as a potential genetic cause of resistance to docetaxel, which may support testing of specific drugs targeting these alterations.

Combination of androgen deprivation therapy (ADT) with external beam radiation therapy (EBRT) is a standard of care for patients with intermediate-risk prostate cancer (PCa). However, 6 months of ADT generates multiple side effects impacting quality of life (QoL). Darolutamide (an androgen receptor targeting agent [ARTA]) is associated with low blood-brain barrier penetrance and less drug-drug interaction.

To assess the efficacy of a combination of 6 months of darolutamide with EBRT to treat patients with unfavorable intermediate-risk PCa.

The DARIUS trial is a multicenter randomized non comparative phase 2 trial, randomizing the 6-months darolutamide + EBRT arm versus 6-months ADT + EBRT in patients with unfavorable intermediate-risk PCa.

The primary endpoint is a biological response defined as prostate-specific antigen ≤0.1 ng/ml at month six of darolutamide or ADT. The key secondary endpoints are biochemical recurrence-free survival, disease-free survival, safety, and QoL. Ancillary studies using radiomics and genomic classifier are planned. Sixty-two patients will be included.

In this population of patients requiring ADT combined with EBRT, the use of an ARTA alone, such as darolutamide, may demonstrate antitumoral efficacy while minimizing toxicity and maintaining QoL. Limitations are mainly inherent to the open-label design of this study.

Six months of darolutamide + EBRT compared with 6 months of ADT + EBRT may be efficient in terms of a biological response, avoiding toxicity and altered QoL attributable to ADT in patients with unfavorable intermediate-risk PCa.

The ongoing DARIUS clinical trial assesses short-term (6 months) darolutamide treatment in association with external beam radiation therapy in men with localized prostate cancer. The trial investigates whether single-agent darolutamide can improve the biological response while maintaining a favorable tolerability profile.

The CABASTY study showed that more frequent administration of a lower dose of cabazitaxel (CBZ) reduced toxicity in older men with metastatic castration-resistant prostate cancer (mCRPC), without compromising efficacy. Here, we investigated the impact of a biweekly CBZ schedule on patient-reported pain and health-related quality of life (HRQoL).

We randomized 196 patients from 25 centers (1:1, stratified by age and G8 score) to the biweekly CBZ16 (CBZ 16 mg/m2) experimental arm or the triweekly CBZ25 (CBZ 25 mg/m2) control arm (CABASTY study, NCT02961257). We assessed pain using the Numeric Pain Rating Scale and HRQoL using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire.

A total of 141 patients were available for a pain and 160 for an HRQoL analysis. Median time to pain progression (stratified hazard ratio [HR]: 1.7, confidence interval [CI]: 0.67-4.22, p = 0.3) and median time to first opiate use (stratified HR: 1.05, CI: 0.44-2.55, p = 0.9) did not differ between arms. We did not see a significant difference in median time to deterioration of FACT-P total score between treatments (stratified HR: 0.88, CI: 0.47-1.7, p = 0.7). Interestingly, the time to onset of several adverse events was significantly longer in the biweekly CBZ16 group.

HRQoL did not significantly differ between the biweekly CBZ16 and the standard schedule. Additionally, onset of some adverse events was delayed. These results may increase health care providers' confidence in using CBZ in older patients with mCRPC who are denied chemotherapy.

Androgen receptor pathway inhibitors are often preferred to taxane chemotherapy as a treatment of second or subsequent line in older metastatic castration-resistant prostate cancer patients due to more frequent treatment-related toxicities. Here, we showed that quality of life and pain did not differ significantly with an adapted schedule of cabazitaxel (CBZ), compared with the standard regimen. This CBZ schedule could increase eligibility of older patients for chemotherapy.

Neuroendocrine prostate cancer (NEPC) encompasses pure NEPC and tumors with mixed adenocarcinoma and neuroendocrine histology. While NEPC is thought to confer a poor prognosis, outcome data are sparse, making risk stratification and treatment decisions difficult for clinicians.

This retrospective study identified patients with morphological and/or immunohistochemical NEPC features on pathological review of high-grade prostate cancer cases. Median overall survival (OS) was calculated by stage and castration sensitivity. Prognostic factors were assessed via multivariate analysis. OS and progression-free survival on first-line metastatic systemic treatment were also evaluated.

Of 135 NEPC cases, 25.9% had NEPC documented in the original pathological report. Mixed pathology was found in 91.9% of cases. Median OS from NEPC diagnosis was 59.2, 42.3, 14.3, 17.6 and 9.6 months for localized, nonmetastatic castration-sensitive, nonmetastatic castration-resistant, metastatic castration-sensitive and metastatic castration-resistant prostate cancer, respectively. Anemia (hazard ratio [HR]: 1.66; 95% CI 1.05-2.16; P = .031) and elevated neutrophil-lymphocyte ratio (NLR) (HR: 1.51; 95% CI 1.01-2.52; P = .045), were associated with increased risk of death on multivariate analysis. 67 patients received first-line metastatic treatment beyond androgen deprivation, with a median progression-free survival of 5.2 months and OS of 15 months. Of these, 50.7% received more than 1 line of systemic treatment.

We observed underdiagnosis of NEPC in pathology specimens. NEPC is associated with poorer prognosis than would be expected in pure adenocarcinoma populations, with rapid progression on first-line metastatic treatment and sharp drop-off between subsequent treatment lines. Anemia and elevated NLR were associated with poor survival.

The recent evidences provided in metastatic hormone sensitive prostate cancer (nmHSPC) and in nonmetastatic castration resistant (nmCRPC) introduced the possibility to adopt Androgen Receptor Signaling inhibitor (ARSi) alone (both settings) or with chemotherapy (in mHSPC). In daily clinical practice there are some opening questions regarding the inclusion of next generation imaging, mainly PSMA-PET, how integrate local treatment as radiotherapy, how to select patients or drugs in a multiple-choice scenario, and how to manage patients with comorbidities and polypharmacy. These issues led the Italian Society for Uro-Oncology (SIUrO) to develop a consensus project involving all of the most important Italian scientific societies engaged in the multidisciplinary and multiprofessional management of the disease. This paper describes the items and statements approved, with the aim to support clinicians in managing metastatic hormone sensitive and nonmetastatic castration resistant prostate cancer patients.

Cardiovascular disease is common in patients with prostate cancer and is an important cause of death. Cardiovascular risk factors are frequent in this population and are often not addressed to thresholds recommended by cardiovascular practice guidelines. Androgen deprivation therapy (ADT) reduces muscle strength and increases adiposity, thereby increasing the risk of diabetes and hypertension, although its relationship with adverse cardiovascular events requires confirmation. Androgen receptor signaling inhibitors and CYP17A1 inhibitors may confer incremental risks of hypertension and cardiovascular events to ADT. Lower cardiovascular risk with gonadotropin-releasing hormone antagonists as compared with agonists requires prespecified randomized clinical trial confirmation.

Metastatic castration-resistant prostate cancer (mCRPC) treatment is advancing yet Nordic, real-world evidence for its use is scarce. In this population-based cohort study, we describe characteristics of patients with mCRPC, and their treatment patterns and survival outcomes in Finland.

Incident patients with mCRPC diagnosed during 2013-2021 were identified from data lakes in two large and representative, Finnish hospital districts, and linked to data on drug purchases and causes of death from national registries.

Of a total of 31,307 patients with prostate cancer, 2,475 progressed to mCRPC during 2013-2021. Those who received no life-prolonging treatment(s) (28% overall) were older with more comorbidities than treated patients. After 2018, the proportion of patients who received life-prolonging treatments increased from 61% to 80%. Of those who received treatment before androgen receptor pathway inhibitors (ARPIs) were reimbursed as first-line (1L) treatment for mCRPC in Finland, 68% received docetaxel, 19% abiraterone and 12% enzalutamide 1L; post-reimbursement, 4% received docetaxel, 24% abiraterone and 71% enzalutamide 1L. Median overall survival for treated patients with mCRPC was 28.3 (95% CI: 26.3-30.4) and 38.5 (95% CI: 32.7-42.1) months pre- and post-reimbursement of 1L-ARPIs, respectively.

The ARPI reimbursement status changes significantly influenced treatment patterns for mCRPC in Finland, favouring enzalutamide over docetaxel. This expanded the pool of men eligible for 1L treatment and improved overall survival by a median of 10 months. These findings highlight the importance of health policy decisions in shaping treatment strategies and patient outcomes in prostate cancer.

In the phase 3 IPATential150 trial, ipatasertib addition to abiraterone significantly reduced the risk of disease progression in men with metastatic castration-resistant prostate cancer (mCRPC) with PTEN loss on immunohistochemistry (IHC), but not in the intention-to-treat (ITT) population. Here we report the final overall survival (OS) analysis and present results for prespecified and exploratory biomarker analyses.

Patients were randomized to receive ipatasertib (400 mg once daily) or placebo. All patients received abiraterone (1000 mg once daily) and prednisone (5 mg twice daily). OS was assessed in patients with PTEN loss on IHC and the ITT population. Exploratory biomarker analyses included PTEN status via next-generation sequencing (NGS) and other key genomic alterations.

At final analysis (median follow-up 33.9 mo), ipatasertib addition did not improve OS for patients with PTEN loss in IHC (n = 521; stratified hazard ratio [sHR] 0.94, 95% confidence interval [CI] 0.76-1.17; p = 0.57) or the ITT population (n = 1101; sHR 0.91, 95% CI 0.79-1.07; not formally tested). Exploratory NGS assessments identified subgroups with genomic PTEN loss (n = 208) or PIK3CA/AKT1/PTEN alterations (n = 250), with potentially better outcomes from ipatasertib (HR 0.76, 95% CI 0.54-1.07; and HR 0.70, 95% CI 0.51-0.96, respectively). Limitations include the exploratory nature of the analysis, incomplete availability of NGS data, and potential intrapatient heterogeneity.

Ipatasertib addition to abiraterone did not improve OS for men with mCRPC, regardless of PTEN status on IHC. Exploratory biomarker analyses identified additional genomic alterations of potential clinical relevance for AKT blockade in mCRPC that require further validation in prospective studies.

Androgen receptor (AR) splice variants, of which ARv7 is the most common, are increased in castration-resistant prostate cancer, but the extent to which they drive AR activity is unclear. We generated a subline of VCaP cells (VCaP16) that is resistant to the AR inhibitor enzalutamide (ENZ). AR activity in VCaP16 is driven by ARv7, independently of full-length AR (ARfl), and its cistrome and transcriptome mirror those of ARfl in VCaP cells. ARv7 expression increases rapidly in response to ENZ, but there is a delay in gaining chromatin binding and transcriptional activity, which is associated with increased chromatin accessibility. AR and nuclear factor I (NFI) motifs are most enriched at more accessible sites, and NFIB/X knockdown greatly diminishes ARv7 function. These findings indicate that ARv7 can drive the AR program but that its activity is dependent on adaptations that increase chromatin accessibility to enhance its intrinsically weak chromatin binding.