PURPOSE: Docetaxel resistance is a significant obstacle in the treatment of prostate cancer (PCa), resulting in unfavorable patient prognoses. Intratumoral heterogeneity, often associated with epithelial-to-mesenchymal transition (EMT), has previously emerged as a phenomenon that facilitates adaptation to various stimuli, thus promoting cancer cell diversity and eventually resistance to chemotherapy, including docetaxel. Hence, understanding intratumoral heterogeneity is essential for better patient prognosis and the development of personalized treatment strategies. METHODS: To address this, we employed a high-throughput single-cell flow cytometry approach to identify a specific surface fingerprint associated with docetaxel-resistance in PCa cells and complemented it with proteomic analysis of extracellular vesicles. We further validated selected antigens using docetaxel-resistant patient-derived xenografts in vivo and probed primary PCa specimens to interrogate of their surface fingerprint. RESULTS: Our approaches revealed a 6-molecule surface fingerprint linked to docetaxel resistance in primary PCa specimens. We observed consistent overexpression of CD95 (FAS/APO-1), and SSEA-4 surface antigens in both in vitro and in vivo docetaxel-resistant models, which was also observed in a cell subpopulation of primary PCa tumors exhibiting EMT features. Furthermore, CD95, along with the essential enzymes involved in SSEA-4 synthesis, ST3GAL1, and ST3GAL2, displayed a significant increase in patients with PCa undergoing docetaxel-based therapy, correlating with poor survival outcomes. CONCLUSION: In summary, we demonstrate that the identified 6-molecule surface fingerprint associated with docetaxel resistance pre-exists in a subpopulation of primary PCa tumors before docetaxel treatment. Thus, this fingerprint warrants further validation as a promising predictive tool for docetaxel resistance in PCa patients prior to therapy initiation.

• MeSH
• chemorezistence * MeSH
• docetaxel * farmakologie   terapeutické užití   MeSH
• epitelo-mezenchymální tranzice účinky léků   MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory prostaty * patologie   farmakoterapie   metabolismus   MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVE: To evaluate the oncological efficacy and safety of sequential intravesical gemcitabine/docetaxel (Gem/Doce) therapy in a European cohort of patients with high-risk and very-high-risk non-muscle-invasive bladder cancer (NMIBC) after previous Bacillus Calmette-Guérin (BCG) treatment. MATERIALS AND METHODS: Data were retrospectively collected from 95 patients with NMIBC, treated with Gem/Doce at 12 European centres between 2021 and 2024. Patients previously treated with BCG who had completed a full induction course and received at least one follow-up evaluation were included. One-year disease-free survival (DFS), high-grade DFS and progression-free survival (PFS) were estimated using Kaplan-Meier curves. Adverse events (AEs) were recorded through medical interviews. RESULTS: Of 75 patients, 63 (84%) were classified as having high-risk and 12 (16%) as having very-high-risk NMIBC. Over a median (interquartile range) follow-up of 9 (5-14) months, 20 patients (27%) relapsed and five (6.7%) underwent radical cystectomy. The 1-year DFS was 73% (95% confidence interval [CI] 62-86%), 1-year high-grade DFS was 79% (95% CI 68-91%) and 1-year PFS was 95% (95% CI 90-100%). AEs occurred in 34 patients (45%), with six (8.7%) experiencing severe AEs. Limitations of the study include the short follow-up and variability in both treatment dwelling times and dosage across centres. CONCLUSION: The intravesical Gem/Doce regimen demonstrated promising short-term oncological outcomes and was well tolerated in this cohort of patients with high- and very-high-risk NMIBC previously treated with BCG. Prospective studies and randomised trials are awaited to define the ideal candidates for Gem/Doce therapy and to standardise treatment protocols.

• MeSH
• aplikace intravezikální MeSH
• BCG vakcína terapeutické užití   MeSH
• deoxycytidin * analogy a deriváty   aplikace a dávkování   škodlivé účinky   MeSH
• docetaxel * aplikace a dávkování   škodlivé účinky   MeSH
• gemcitabin MeSH
• invazivní růst nádoru MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory močového měchýře neinvadující svalovinu MeSH
• nádory močového měchýře * farmakoterapie   patologie   mortalita   MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Geografické názvy
• Evropa MeSH

Kombinovaná léčba metastatického hormonálně senzitivního karcinomu prostaty a sekvenční léčba metastatického kastračně rezistentního karcinomu prostaty významně prodloužila přežití mužů s tímto onemocněním. Pacienti s viscerálními metastázami mají vždy horší prognózu než pacienti s metastázami pouze v kostech. Pacienti s jaterními metastázami mají obvykle nejhorší výsledky přežití ve srovnání s pacienty s kostními metastázami nebo jinými místy viscerálních metastáz.

Combined treatment of metastatic hormone-sensitive prostate cancer and sequential treatment of metastatic castration-resistant prostate cancer significantly prolonged the survival of men with this disease. Patients with visceral metastases invariably have a worse prognosis than patients with bone-only metastase. Patients with liver metastases typically have the worst survival outcomes compared to those with bone metastases or other sites of visceral metastases.

• MeSH
• doba přežití bez progrese choroby MeSH
• docetaxel terapeutické užití   MeSH
• klinická studie jako téma MeSH
• kombinovaná farmakoterapie metody   MeSH
• lidé MeSH
• metastázy nádorů * farmakoterapie   MeSH
• nádory prostaty rezistentní na kastraci farmakoterapie   komplikace   MeSH
• nádory prostaty * farmakoterapie   komplikace   MeSH
• protinádorové látky aplikace a dávkování   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• přehledy MeSH

Metastatický hormonálně senzitivní karcinom prostaty (mHSPC) je různorodé onemocnění vyžadující individuální léčebný přístup. Androgen-deprivační terapie (ADT) je základem terapie diseminovaného onemocnění s velmi dobrou iniciální odpovědí na léčbu u většiny pacientů, ale s limitovaným trváním odpovědi. Léčba ADT v kombinaci s ARTA (androgen receptor targeted agents – abirateron, apalutamid, enzalutamid) významně prodlužuje přežití bez progrese (PFS) i celkové přežití (OS), a stala se tak standardem v léčbě pacientů s mHSPC. Obdobného účinku dosahuje i kombinovaná léčba ADT s docetaxelem, tedy tzv. dublet. U části pacientů s agresivním onemocněním ale tato terapie není dostatečně účinná. Jednou z možností, jak zvýšit účinnost léčby, je kombinace ADT s ARTA a docetaxelem, tedy tzv. triplet. V článku se zaměříme na základní studie týkající se této problematiky a pokusíme se definovat pacienty, pro které je tato kombinovaná léčba výhodná.

Metastatic hormone-sensitive prostate cancer is a diverse disease requiring an individual treatment approach. Androgen deprivation therapy (ADT) is the mainstay of treatment for disseminated disease with a very good initial response to treatment in most patients, but with a limited duration of response. Combined treatment with ADT and ARTA (androgen receptor targeted agents – abiraterone, apalutamide, enzalutamide) significantly prolongs progression-free survival (PFS) and overall survival (OS) and has thus become the standard of treatment for patients with mHSPC. A similar effect is achieved by combined treatment with ADT and docetaxel, the so-called doublet therapy. However, this treatment is not effective enough for some patients with aggressive disease. One possibility to increase the effectiveness of treatment is the combination of ADT with ARTA and docetaxel, the socalled triplet therapy. In this article, we will focus on basic studies regarding this issue and try to define patients for whom this combined treatment is beneficial.

• Klíčová slova
• darolutamid,
• MeSH
• abirateron terapeutické užití   MeSH
• antagonisté androgenů * terapeutické užití   MeSH
• docetaxel terapeutické užití   MeSH
• kombinovaná terapie * metody   MeSH
• lidé MeSH
• metastázy nádorů farmakoterapie   MeSH
• nádory prostaty * farmakoterapie   MeSH
• pyrazoly terapeutické užití   MeSH
• Check Tag
• lidé MeSH

BACKGROUND: Triplet therapy, androgen receptor signaling inhibitors (ARSIs) plus docetaxel plus androgen-deprivation therapy (ADT), is a novel guideline-recommended treatment for metastatic hormone-sensitive prostate cancer (mHSPC). However, the optimal selection of the patient most likely to benefit from triplet therapy remains unclear. METHODS: We performed a systematic review, meta-analysis, and network meta-analysis to assess the oncologic benefit of triplet therapy in mHSPC patients stratified by disease volume and compare them with doublet treatment regimens. Three databases and meeting abstracts were queried in March 2023 for randomized controlled trials (RCTs) evaluating patients treated with systemic therapy for mHSPC stratified by disease volume. Primary interests of measure were overall survival (OS). We followed the PRISMA guideline and AMSTAR2 checklist. RESULTS: Overall, eight RCTs were included for meta-analyses and network meta-analyses (NMAs). Triplet therapy outperformed docetaxel plus ADT in terms of OS in both patients with high-(pooled HR: 0.73, 95%CI 0.64-0.84) and low-volume mHSPC (pooled HR: 0.71, 95%CI 0.52-0.97). There was no statistically significant difference between patients with low- vs. high-volume in terms of OS benefit from adding ARSI to docetaxel plus ADT (p = 0.9). Analysis of treatment rankings showed that darolutamide plus docetaxel plus ADT (90%) had the highest likelihood of improved OS in patients with high-volume disease, while enzalutamide plus ADT (84%) had the highest in with low-volume disease. CONCLUSIONS: Triplet therapy improves OS in mHSPC patients compared to docetaxel-based doublet therapy, irrespective of disease volume. However, based on treatment ranking, triplet therapy should preferably be considered for patients with high-volume mHSPC while those with low-volume are likely to be adequately treated with ARSI + ADT.

• MeSH
• antagonisté androgenních receptorů terapeutické užití   MeSH
• antagonisté androgenů * terapeutické užití   MeSH
• docetaxel * terapeutické užití   aplikace a dávkování   MeSH
• lidé MeSH
• nádory prostaty * farmakoterapie   mortalita   patologie   MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   MeSH
• randomizované kontrolované studie jako téma MeSH
• síťová metaanalýza * MeSH
• tumor burden MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• systematický přehled MeSH

STUDY AIM: ModraDoc006, an oral formulation of docetaxel, is co-administered with the cytochrome P450-3A4 and P-glycoprotein inhibitor, ritonavir (r): ModraDoc006/r. The preliminary efficacy and safety of oral ModraDoc006/r was evaluated in a global randomized phase II trial and compared to the current standard chemotherapy regimen of intravenous (i.v.) docetaxel and prednisone. METHODS: 103 mCRPC patients, chemotherapy-naïve with/without abiraterone and/or enzalutamide pretreated, with adequate organ function and evaluable disease per RECIST v1.1 and PCWG3 guidelines were randomized 1:1 into two cohorts. In Cohort 1, 49 patients received docetaxel 75 mg/m2 i.v. every 3 weeks (Q3W). In Cohort 2, 52 patients received ModraDoc006/r; 21 patients with a starting dose of ModraDoc006 30 mg with ritonavir 200 mg in the morning and ModraDoc006 20 mg with ritonavir 100 mg in the evening (30-20/200-100 mg) bi-daily-once-weekly (BIDW) on Days 1, 8, and 15 of a 21-day cycle. To alleviate tolerability, the starting dose was amended to ModraDoc006/r 20-20/200-100 mg in another 31 patients. All patients received prednisone 10 mg daily. Primary endpoint was rPFS. RESULTS: There was no significant difference in rPFS between the 2 arms (p = 0.1465). Median rPFS was 9.5 months and 11.1 months (95% CI) for ModraDoc006/r and i.v. docetaxel, respectively. Partial response was noted in 44.1% and 38.7% measurable disease patients, and 50% decline of PSA was seen in 23 (50%) and 26 (56.5%) evaluable cases treated with ModraDoc006/r and i.v. docetaxel, respectively. The safety profile of ModraDoc006/r 20-20/200-100 mg dose was significantly better than i.v. docetaxel, with mild (mostly Grade 1) gastrointestinal toxicities, no hematologic adverse events, and neuropathy and alopecia incidence of 11.5% and 25%, respectively. CONCLUSIONS: ModraDoc006/r potentially represents a widely applicable, convenient, effective, and better tolerated oral taxane therapy option for mCRPC. Further investigation of ModraDoc006/r in a large randomized trial is warranted.

• MeSH
• docetaxel terapeutické užití   MeSH
• lidé MeSH
• nádory prostaty rezistentní na kastraci * farmakoterapie   patologie   MeSH
• prednison MeSH
• přemostěné cyklické sloučeniny * MeSH
• prostatický specifický antigen MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   MeSH
• ritonavir škodlivé účinky   MeSH
• taxoidy terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• randomizované kontrolované studie MeSH

• MeSH
• abirateron farmakologie   terapeutické užití   MeSH
• analýza přežití MeSH
• docetaxel farmakologie   terapeutické užití   MeSH
• klinická studie jako téma MeSH
• lidé MeSH
• metaanalýza jako téma MeSH
• metastázy nádorů MeSH
• nádory prostaty * farmakoterapie   MeSH
• protokoly protinádorové kombinované chemoterapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH

• Klíčová slova
• darolutamid,
• MeSH
• antagonisté androgenů aplikace a dávkování   terapeutické užití   MeSH
• docetaxel aplikace a dávkování   terapeutické užití   MeSH
• lidé MeSH
• nádory prostaty * diagnóza   farmakoterapie   MeSH
• prostatický specifický antigen krev   MeSH
• protokoly protinádorové kombinované chemoterapie aplikace a dávkování   terapeutické užití   MeSH
• pyrazoly aplikace a dávkování   terapeutické užití   MeSH
• randomizované kontrolované studie jako téma MeSH
• Check Tag
• lidé MeSH

PURPOSE OF REVIEW: Shortages in intravesical Bacillus Calmette-Guérin (BCG) immunotherapy represent a challenge in the management of high-risk nonmuscle invasive bladder cancer (HR-NMIBC). This study aimed to review the efficacy and safety of intravesical gemcitabine (GEM) and docetaxel (DOCE) for BCG-naive and unresponsive HR-NMIBC. RECENT FINDINGS: We identified six studies eligible for quantitative analysis through a systematic search according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement. In the two studies in the BCG-naive setting, 1-year and 2-year pooled recurrence-free survival (RFS) were 86 and 84%, respectively. In the two studies in the BCG unresponsive setting, 6-month, 1-year and 2-year pooled high-grade recurrence-free survival (HG-RFS) were 80, 66 and 51%, respectively. Cumulative data from four studies revealed that 2.3% of patients could not complete induction therapy and 6.9% experienced treatment delay or dose reduction due to adverse events. SUMMARY: Despite the preliminary data and based on a small sample size, intravesical GEM/DOCE therapy is a highly promising combination yielding an effective and well tolerated alternative to BCG when indicated. Further large, well designed comparative studies with BCG are needed.

• MeSH
• adjuvancia imunologická MeSH
• aplikace intravezikální MeSH
• BCG vakcína škodlivé účinky   MeSH
• docetaxel terapeutické užití   MeSH
• gemcitabin * MeSH
• invazivní růst nádoru MeSH
• lidé MeSH
• lokální recidiva nádoru MeSH
• nádory močového měchýře * terapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• systematický přehled MeSH

• Klíčová slova
• sotorasib, mutace KRAS, studie CodeBreak200,
• MeSH
• docetaxel * farmakologie   terapeutické užití   MeSH
• inhibitory kontrolních bodů * farmakologie   terapeutické užití   MeSH
• klinická studie jako téma MeSH
• lidé MeSH
• nemalobuněčný karcinom plic farmakoterapie   MeSH
• protinádorové látky MeSH
• Check Tag
• lidé MeSH