BACKGROUND AND OBJECTIVE: Apalutamide (APA) is a treatment for metastatic castration-sensitive prostate cancer (mCSPC). In the ARON-3 study we investigated real-world experiences with APA treatment for mCSPC. METHODS: We retrospectively assessed real-world clinical outcomes for patients with mCSPC treated with APA in the ARON-3 study. Overall survival (OS) was calculated from APA initiation to death from any cause. PSA90 was defined as a prostate-specific antigen decline of ≥90% from baseline, and PSA0.2 as achievement of a PSA level ≤0.2 ng/ml. Data for adverse events were retrospectively collected from electronic and paper charts and categorized according to Common Terminology Criteria for Adverse Events v5.0. KEY FINDINGS AND LIMITATIONS: We included 531 patients with mCSPC treated with APA. High-volume disease was reported for 214 patients (40%), and 56 (11%) had visceral metastases. Median OS was not reached. PSA90 was experienced by 461 patients (87%) and PSA0.2 by 368 (69%). Median OS was significantly longer for patients with PSA90 or PSA0.2 than for subjects without these responses (p < 0.001). The incidence of grade 3-4 fatigue was higher among elderly patients (≥80 yr) than among younger patients (19% vs 5%), but the incidence of other adverse events was comparable between the age groups. CONCLUSIONS AND CLINICAL IMPLICATIONS: APA is an effective and tolerable treatment for mCSPC in the real-world setting. PATIENT SUMMARY: The ARON-3 project collects data for patients with prostate cancer treated in multiple centers worldwide to assess outcomes in the real-world setting. We analyzed data for patients with metastatic hormone-sensitive prostate cancer receiving apalutamide. Our results show that apalutamide is a safe and effective drug in the real-world setting as well as in clinical trials.

• MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádory prostaty rezistentní na kastraci farmakoterapie   patologie   mortalita   MeSH
• prostatický specifický antigen krev   MeSH
• protinádorové látky terapeutické užití   MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• thiohydantoiny * terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH

BACKGROUND: Androgen-receptor signaling inhibitors (ARSIs) significantly improve survival in systemic therapy for advanced/metastatic prostate cancer (PCa) patients; however possible central nervous system (CNS) toxicity is an unaddressed concern. We aimed to assess and compare the incidence of CNS-related adverse events (AEs) secondary to the treatment of PCa patients with different ARSIs. MATERIALS: In August 2023, a comprehensive seach was conducted in three databases for randomized controlled trials (RCTs) of PCa patients receiving ARSIs plus ADT. The primary endpoints included mental impairment, cognitive impairment, seizure, fatigue, and falls. RESULTS: Twenty-six RCTs, comprising 20,328 patients, were included in meta-analyses and network meta-analyses (NMAs). ARSIs increased the risk of mental impairment (RR: 1.72; 95% CI, 1.09-2.71), cognitive impairment (RR: 2.25; 95% CI, 1.78-2.86), seizure (RR: 2.20, 95% CI, 1.09-4.45), fatigue (RR: 1.31, 95% CI, 1.20-1.43), and falls (RR: 2.07, 95% CI, 1.60-2.67) compared to standard of care (SOC). Based on NMAs, Enzalutamide showed a significant increase in risk for all assessed CNS-related AEs, while Abiraterone demonstrated significant risk increases in cognitive impairment, fatigue, and falls. Conversely, Darolutamide did not exhibit significant increases in risk for any CNS-related AEs, except for fatigue. CONCLUSIONS: The addition of ARSIs to ADT increased all examined CNS-related AEs compared to SOC. Each ARSI is associated with a distinct profile of CNS-related AEs. Careful patient selection and monitoring for CNS sequelae is necessary to achieve the best quality of life in patients on ARSI + ADT for PCa.

• MeSH
• antagonisté androgenních receptorů * škodlivé účinky   aplikace a dávkování   terapeutické užití   MeSH
• benzamidy MeSH
• fenylthiohydantoin škodlivé účinky   aplikace a dávkování   MeSH
• lidé MeSH
• nádory prostaty * farmakoterapie   patologie   MeSH
• nemoci centrálního nervového systému chemicky indukované   MeSH
• nitrily MeSH
• pyrazoly MeSH
• randomizované kontrolované studie jako téma MeSH
• síťová metaanalýza * MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• přehledy MeSH
• systematický přehled MeSH

BACKGROUND: Androgen-receptor pathway inhibitors (ARPIs) have dramatically changed the management of advanced/metastatic prostate cancer (PCa). However, their cardiovascular toxicity remains to be clarified. OBJECTIVE: To analyze and compare the risks of cardiovascular events secondary to treatment of PCa patients with different ARPIs. METHODS: In August 2023, we queried PubMed, Scopus, and Web of Science databases to identify randomized controlled studies (RCTs) that analyze PCa patients treated with abiraterone, apalutamide, darolutamide, and enzalutamide. The primary outcomes of interest were the incidence of cardiac disorder, heart failure, ischemic heart disease (IHD), atrial fibrillation (AF), and hypertension. Network meta-analyses (NMAs) were conducted to compare the differential outcomes of each ARPI plus androgen deprivation therapy (ADT) compared to standard of care (SOC). RESULTS: Overall, 26 RCTs were included. ARPIs were associated with an increased risk of cardiac disorders (RR: 1.74, 95% CI: 1.13-2.68, p = 0.01), heart failure (RR: 2.49, 95% CI: 1.05-5.91, p = 0.04), AF (RR: 2.15, 95% CI: 1.14-4.07, p = 0.02), and hypertension (RR: 2.06, 95% CI: 1.67-2.54, p < 0.01) at grade ≥3. Based on NMAs, abiraterone increased the risk of grade ≥3 cardiac disorder (RR:2.40, 95% CI: 1.42-4.06) and hypertension (RR:2.19, 95% CI: 1.77-2.70). Enzalutamide was associated with the increase of grade ≥3 AF(RR: 3.17, 95% CI: 1.05-9.58) and hypertension (RR:2.30, 95% CI: 1.82-2.92). CONCLUSIONS: The addition of ARPIs to ADT increases the risk of cardiac disorders, including IHD and AF, as well as hypertension. Each ARPI exhibits a distinct cardiovascular event profile. Selecting patients carefully and vigilant monitoring for cardiovascular issues is imperative for those undergoing ARPI + ADT treatment.

• MeSH
• androsteny MeSH
• antagonisté androgenních receptorů * škodlivé účinky   terapeutické užití   MeSH
• benzamidy škodlivé účinky   MeSH
• fenylthiohydantoin MeSH
• kardiovaskulární nemoci * chemicky indukované   epidemiologie   MeSH
• lidé MeSH
• nádory prostaty * farmakoterapie   patologie   MeSH
• nitrily škodlivé účinky   MeSH
• randomizované kontrolované studie jako téma MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• síťová metaanalýza MeSH
• systematický přehled MeSH

• Klíčová slova
• enzalutamid,
• MeSH
• antagonisté androgenů terapeutické užití   MeSH
• benzamidy terapeutické užití   MeSH
• fenylthiohydantoin terapeutické užití   MeSH
• lidé MeSH
• nádory prostaty * farmakoterapie   MeSH
• nitrily terapeutické užití   MeSH
• prostatický specifický antigen MeSH
• protinádorové látky aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• protokoly protinádorové kombinované chemoterapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• randomizované kontrolované studie MeSH

• MeSH
• benzamidy terapeutické užití   MeSH
• fenylthiohydantoin terapeutické užití   MeSH
• kvalita života MeSH
• leuprolid aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• lidé MeSH
• nádory prostaty * farmakoterapie   komplikace   MeSH
• nitrily terapeutické užití   MeSH
• protinádorové látky aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• průzkumy a dotazníky MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• klinická studie MeSH

• Klíčová slova
• enzalutamid,
• MeSH
• antagonisté androgenů aplikace a dávkování   terapeutické užití   MeSH
• benzamidy MeSH
• fenylthiohydantoin MeSH
• leuprolid aplikace a dávkování   terapeutické užití   MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   MeSH
• nádory prostaty * farmakoterapie   MeSH
• nitrily MeSH
• prostatický specifický antigen MeSH
• randomizované kontrolované studie jako téma MeSH
• Check Tag
• lidé MeSH

BACKGROUND AND OBJECTIVE: In prostate cancer treated with androgen deprivation therapy (ADT), the initial sign of treatment resistance is often prostate-specific antigen (PSA) progression, followed by radiographic progression. However, the association between these two forms of progression remains unclear, especially in patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with androgen receptor pathway inhibitors. We sought to evaluate the association between radiographic progression, PSA progression, and outcomes of apalutamide therapy in mCSPC. METHODS: We analyzed individual participant-level data for patients randomized within the TITAN trial who experienced radiographic progression during follow-up (N = 326). This study investigated radiographic progression without simultaneous or preceding PSA progression, as defined by the Prostate Cancer Working Group 2 (discordant progression), and explored the association of such progression with radiographic progression-free survival. KEY FINDINGS AND LIMITATIONS: Among the patients who developed radiographic progression, 115 (35.3%) had been treated with apalutamide plus ADT (the apalutamide group) and 211 (64.7%) with placebo plus ADT (the placebo group). Discordant progression occurred in 52.2% of patients (60 of 115) in the apalutamide group and 27.5% (58 of 211) in the placebo group (p < 0.001). A multivariable logistic regression analysis showed that discordant progression was associated with apalutamide treatment. We found evidence of an association between discordant progression and shorter radiographic progression-free survival. CONCLUSIONS AND CLINICAL IMPLICATIONS: This study found that nearly half of the patients with mCSPC treated with apalutamide who experienced radiographic progression developed it without corresponding PSA progression, suggesting that heavy reliance on PSA monitoring may be inadequate for assessing disease activity in this context. PATIENT SUMMARY: In patients who have metastatic castration-sensitive prostate cancer (mCSPC) and are being treated with apalutamide, radiographic images may show cancer progression even if prostate-specific antigen tests indicate no change. This highlights the importance of regular imaging when using apalutamide to manage mCSPC.

• MeSH
• antagonisté androgenů terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádory prostaty rezistentní na kastraci farmakoterapie   patologie   krev   diagnostické zobrazování   MeSH
• progrese nemoci * MeSH
• prostatický specifický antigen * krev   MeSH
• senioři MeSH
• thiohydantoiny * terapeutické užití   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH

Ve vyspělých zemích je stále více pacientů léčeno DOAC, jejichž užívání na rozdíl od dosud podávaného warfarinu nelze v běžné lékařské praxi jednoduše titrovat. Důležité je tedy při dávkování DOAC postupovat podle doporučení vydaných držiteli registračních rozhodnutí v SmPC a doporučených postupů vydávaných odbornými společnostmi lékařů se zohledněním stavu jednotlivých pacientů. Lékové interakce DOAC konkrétními protizáchvatovými léky mohou u některých pacientů způsobit snížení antikoagulačního působení a z nových studií vyplývá, že může dojít i ke zvýšení rizika krvácivých příhod, například při kombinaci kyseliny valproové s DOAC. Tento článek přináší přehled současných znalostí o této problematice.

In developed countries, more and more patients are being treated with DOACs, the use of which, unlike until recently preferred warfarin, cannot be easily titrated in common medical practice. It is therefore important, when dosing DOACs, to follow the recommendations issued by the marketing autorisation holders in SmPC and guidelines issued by professional societies of physicians, taking into account the condition of individual patients. Drug interactions of DOACs with specific anticonvulsants may cause a reduction in anticoagulant effect in some patients, and new studies suggest that there may also be an increased risk of bleeding events, for example valproic acid and DOACs. This article provides an overview of the current knowledge on this issue.

• MeSH
• antikoagulancia * aplikace a dávkování   farmakokinetika   krev   škodlivé účinky   MeSH
• antikonvulziva * farmakologie   škodlivé účinky   MeSH
• embolie a trombóza chemicky indukované   epidemiologie   MeSH
• fenytoin škodlivé účinky   MeSH
• karbamazepin škodlivé účinky   MeSH
• klinická studie jako téma MeSH
• krvácení chemicky indukované   epidemiologie   MeSH
• lékové interakce MeSH
• lidé MeSH
• nežádoucí účinky léčiv epidemiologie   MeSH
• riziko MeSH
• statistika jako téma MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• kazuistiky MeSH
• přehledy MeSH

BACKGROUND: Investigation remains incomplete regarding potential variations in the effect of androgen receptor pathway inhibitors, including apalutamide, based on baseline tumor burden in patients with metastatic castration-sensitive prostate cancer (mCSPC). METHODS: The authors analyzed individual participant-level data from 1052 patients with mCSPC who were randomized in the TITAN trial (apalutamide vs. placebo, both with androgen-deprivation therapy). Outcomes included radiographic progression-free survival (PFS), second PFS (PFS2), and overall survival (OS). Multivariable Cox proportional hazards regression models, with and without restricted cubic splines, were used to determine the association between apalutamide benefit and bone metastasis count or visceral metastasis. Subgroup treatment effects were quantified based on inverse probability of treatment weighting-adjusted hazard ratios (HRs). RESULTS: Analysis using restricted cubic splines indicated that apalutamide provided less benefit for PFS2 and OS in patients with fewer bone metastases. The authors also found evidence of a heterogeneous effect of apalutamide on PFS2 and OS between patients with two or less bone metastases and those with three or more bone metastases. In patients who had two or less bone metastases, there was no evidence of a benefit from apalutamide for radiographic PFS (HR, 0.65; 95% confidence interval [CI], 0.35-1.22), PFS2 (HR, 1.18; 95% CI, 0.66-2.12), or OS (HR, 1.05; 95% CI, 0.60-1.83). No evidence of an association was noted between visceral metastasis and apalutamide benefit. CONCLUSIONS: The addition of apalutamide to androgen-deprivation therapy may provide less benefit in patients with mCSPC who have fewer bone metastases. Counting baseline bone metastases may help identify optimal candidates for apalutamide treatment of mCSPC. CLINICAL TRIALS REGISTRATION: NCT02489318 PLAIN LANGUAGE SUMMARY: In an analysis of individual participant data from a trial (the TITAN trial) in patients with metastatic (spreading) castration-sensitive prostate cancer, treatment intensification based on the addition new drugs to standard androgen-deprivation therapy (ADT) was analyzed and compared with the effects in patients who received only standard ADT. Compared with ADT alone, the survival benefit of adding the new drug apalutamide to standard ADT varied according to the number of bone metastases, but no association was observed between the spread of cancer to soft tissues and organs and a survival benefit from adding apalutamide. The results indicate that counting the number of bone metastases may help identify which patients with metastatic castration-sensitive prostate cancer are optimal candidates for treatment intensification with the addition of apalutamide to standard ADT.

• MeSH
• antagonisté androgenních receptorů terapeutické užití   MeSH
• antagonisté androgenů terapeutické užití   MeSH
• doba přežití bez progrese choroby MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádory kostí sekundární   farmakoterapie   MeSH
• nádory prostaty rezistentní na kastraci farmakoterapie   patologie   mortalita   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• thiohydantoiny * terapeutické užití   aplikace a dávkování   MeSH
• tumor burden * účinky léků   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH

Androgen receptor-targeting agents, particularly enzalutamide, show promise in enhancing prostate cancer diagnostic and therapeutic strategies by modulating prostate-specific membrane antigen (PSMA). Methods: A retrospective clinical cohort study investigated 9 men with metastatic castration-resistant prostate cancer on enzalutamide. PSMA PET/CT scans were obtained before and after enzalutamide initiation to assess PSMA expression changes. Lesions and organs at risk were evaluated visually and semiquantitatively. The flare phenomenon was characterized by a significant increase (≥20%) in the SUVmax of existing lesions or the appearance of new PSMA-positive lesions. Results: Exposure to enzalutamide led to a significant PSMA expression increase in 56% of assessed lesions (n = 42), with new lesions detected in 1 patient (11%). PSMA expression in organs at risk remained largely unaffected, indicating a tumor-specific response. Conclusion: Enzalutamide induces PSMA upregulation in metastatic castration-resistant prostate cancer, potentially enhancing diagnostic and therapeutic strategies. Further exploration of the flare phenomenon's clinical implications is warranted.

• MeSH
• antigeny povrchové * metabolismus   MeSH
• benzamidy * MeSH
• fenylthiohydantoin * terapeutické užití   analogy a deriváty   MeSH
• glutamátkarboxypeptidasa II * metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory prostaty rezistentní na kastraci * farmakoterapie   diagnostické zobrazování   metabolismus   MeSH
• nitrily * terapeutické užití   MeSH
• PET/CT * MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• upregulace * MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH