Metastazující kastračně rezistentní karcinom prostaty (metastatic castration resistant prostate cancer, mCRPC) představuje nejzávažnější formu široké skupiny karcinomů prostaty. Je typický rezistencí k primární androgen deprivační terapii, proto je pro účinnou léčbu nutné rozšířit léčebné spektrum. Čím více linií terapie použijeme, tím lze život pacientů s mCRPC více prodloužit. Jednou z léčebných možností je i cílená léčba. Inhibitory poly(ADP-ribóza) polymerázy (PARP) prokázaly u těchto pacientů účinnost jednak v monoterapii, jednak v kombinaci s léčbou cílenou na androgenní receptor. Článek se věnuje postavení inhibitoru PARP talazoparibu v léčbě mCRPC.

Metastatic castration resistant prostate cancer (mCRPC) represents the most severe form of a group of prostate cancer. It is characterized by resistance to primary androgen deprivation therapy, which necessitates the expansion of the treatment spectrum for effective management. The more lines of therapy we use, the more we can prolong the survival of patients with mCRPC. One of the treatment options is targeted therapy. Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated efficacy, both in monotherapy and in combination with androgen receptor targeted therapy in these patients. The article discusses the role of the PARP inhibitor talazoparib in the treatment of mCRPC.

BACKGROUND/AIM: New generation androgen receptor-targeting agents (ARTA) have been in the spotlight for their efficacy in metastatic castration-resistant prostate cancer (mCRPC). Prostate-specific antigen (PSA) represents one of the most commonly used serum cancer biomarkers worldwide. The present retrospective study focused on the prognostic role of serum PSA isoforms and their early dynamics in mCRPC patients treated with abiraterone acetate (ABI) or enzalutamide (ENZ). PATIENTS AND METHODS: The association between outcomes of 334 mCRPC patients treated with ABI or ENZ and the levels of serum total PSA (tPSA), free PSA (fPSA), [-2]proPSA and the Prostate Health Index (PHI) at baseline and one month after treatment initiation was analyzed retrospectively. RESULTS: In the multivariable Cox proportional hazards models, baseline tPSA>50 μg/l (p<0.001), and [-2]proPSA>300 ng/l (p=0.017) remained independent significant factors associated with inferior OS, while baseline fPSA>1.75 μg/l (p=0.050) and Δ [-2]proPSA >-50% approached statistical significance (p=0.062). The results of ROC analyses assessing the ability of baseline tPSA, fPSA, and [-2]proPSA to predict mortality within two years showed area under the curve (AUC) values of 0.709, 0.685, and 0.740, respectively. Among the subgroup with baseline tPSA≤20.0 μg/l, the results of ROC analyses for baseline tPSA, fPSA and [-2]proPSA showed AUC values of 0.441, 0.682, and 0.688, respectively. CONCLUSION: Our results suggest a significant correlation between pretreatment serum levels of tPSA and [-2]proPSA with OS in mCRPC patients receiving ARTA.

• MeSH
• abirateron terapeutické užití   aplikace a dávkování   MeSH
• androgenní receptory * krev   metabolismus   MeSH
• antagonisté androgenních receptorů terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádorové biomarkery krev   MeSH
• nádory prostaty rezistentní na kastraci * farmakoterapie   krev   patologie   mortalita   MeSH
• prognóza MeSH
• prostatický specifický antigen * krev   MeSH
• protein - isoformy * krev   MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři 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

Aryl hydrocarbon receptor (AhR) is a transcription factor that is primarily known as an intracellular sensor of environmental pollution. After five decades, the list of synthetic and toxic chemicals that activate AhR signaling has been extended to include a number of endogenous compounds produced by various types of cells via their metabolic activity. AhR signaling is active from the very beginning of embryonal development throughout the life cycle and participates in numerous biological processes such as control of cell proliferation and differentiation, metabolism of aromatic compounds of endogenous and exogenous origin, tissue regeneration and stratification, immune system development and polarization, control of stemness potential, and homeostasis maintenance. AhR signaling can be affected by various pharmaceuticals that may help modulate abnormal AhR signaling and drive pathological states. Given their role in immune system development and regulation, AhR antagonistic ligands are attractive candidates for immunotherapy of disease states such as advanced prostate cancer, where an aberrant immune microenvironment contributes to cancer progression and needs to be reeducated. Advanced stages of prostate cancer are therapeutically challenging and characterized by decreased overall survival (OS) due to the metastatic burden. Therefore, this review addresses the role of AhR signaling in the development and progression of prostate cancer and discusses the potential of AhR as a drug target for the treatment of advanced prostate cancer upon entering the phase of drug resistance and failure of first-line androgen deprivation therapy.Abbreviation: ADC: antibody-drug conjugate; ADT: androgen deprivation therapy; AhR: aryl hydrocarbon receptor; AR: androgen receptor; ARE: androgen response element; ARPI: androgen receptor pathway inhibitor; mCRPC: metastatic castration-resistant prostate cancer; DHT: 5a-dihydrotestosterone; FICZ: 6-formylindolo[3,2-b]carbazole; 3-MC: 3-methylcholanthrene; 6-MCDF: 6-methyl-1,3,8-trichlorodibenzofuran; MDSCs: myeloid-derived suppressor cells; PAHs: polycyclic aromatic hydrocarbons; PCa: prostate cancer; TAMs: tumor-associated macrophages; TF: transcription factor; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TME: tumor microenvironment; TRAMP: transgenic adenocarcinoma of the mouse prostate; TROP2: tumor associated calcium signal transducer 2.

• MeSH
• cílená molekulární terapie MeSH
• lidé MeSH
• nádorové mikroprostředí účinky léků   MeSH
• nádory prostaty * farmakoterapie   metabolismus   patologie   MeSH
• protinádorové látky * terapeutické užití   farmakologie   MeSH
• receptory aromatických uhlovodíků * metabolismus   antagonisté a inhibitory   MeSH
• signální transdukce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

PURPOSE: Prostate-specific membrane antigen (PSMA) radioligand therapy is a promising treatment for metastatic castration-resistant prostate cancer (mCRPC). Several beta or alpha particle-emitting radionuclide-conjugated small molecules have shown efficacy in late-stage mCRPC and one, [[177Lu]Lu]Lu-PSMA-617, is FDA approved. In addition to tumor upregulation, PSMA is also expressed in kidneys and salivary glands where specific uptake can cause dose-limiting xerostomia and potential for nephrotoxicity. The PSMA inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) can prevent kidney uptake in mice, but also blocks tumor uptake, precluding its clinical utility. Preferential delivery of 2-PMPA to non-malignant tissues could improve the therapeutic window of PSMA radioligand therapy. METHODS: A tris(isopropoxycarbonyloxymethyl) (TrisPOC) prodrug of 2-PMPA, JHU-2545, was synthesized to enhance 2-PMPA delivery to non-malignant tissues. Mouse pharmacokinetic experiments were conducted to compare JHU-2545-mediated delivery of 2-PMPA to plasma, kidney, salivary glands, and C4-2 prostate tumor xenograft. Imaging studies were conducted in rats and mice to measure uptake of PSMA PET tracers in kidney, salivary glands, and prostate tumor xenografts with and without JHU-2545 pre-treatment. RESULTS: JHU-2545 resulted in approximately 3- and 53-fold greater exposure of 2-PMPA in rodent salivary glands (18.0 ± 0.97 h*nmol/g) and kidneys (359 ± 4.16 h*nmol/g) versus prostate tumor xenograft (6.79 ± 0.19 h*nmol/g). JHU-2545 also blocked rodent kidneys and salivary glands uptake of the PSMA PET tracers [68Ga]Ga-PSMA-11 and [18 F]F-DCFPyL by up to 85% with little effect on tumor. CONCLUSIONS: JHU-2545 pre-treatment may enable greater cumulative administered doses of PSMA radioligand therapy, possibly improving safety and efficacy.

• MeSH
• antigeny povrchové * metabolismus   MeSH
• glutamátkarboxypeptidasa II * metabolismus   MeSH
• krysa rodu rattus MeSH
• ledviny * diagnostické zobrazování   metabolismus   MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• organofosforové sloučeniny MeSH
• slinné žlázy * diagnostické zobrazování   metabolismus   účinky záření   MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: The European Association of Urology guidelines include the lutetium-177 (177Lu) PSMA-617 prostate-specific membrane antigen (PSMA) ligand as a therapy option for metastatic castration-resistant prostate cancer (mCRPC). A major challenge in clinical practice is to pursue a personalized treatment approach based on robust predictive biomarkers. OBJECTIVE: To assess the performance of 177Lu PSMA in real-world practice and to elaborate clinical biomarkers for evaluating treatment responses. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective observational study including 233 patients with mCRPC treated with 177Lu PSMA in eight high-volume European centers. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline characteristics and clinical parameters during and after 177Lu PSMA treatment were documented. Correlations to treatment response were analyzed using χ2 and log-rank tests, with differences between groups with and without disease progression calculated using a Mann-Whitney U test. Univariate and multivariate-adjusted hazard ratios (HRs) were measured using Cox proportional hazards models. RESULTS AND LIMITATIONS: A prostate-specific antigen (PSA) decrease of ≥30% was observed in 41.7%, 63.5%, and 77.8% of patients after the first, second, and third treatment cycle, respectively. Restaging performed via PSMA positron emission tomography-computed tomography revealed that 33.7% of patients had an imaging-based response, including two patients with a complete response, while 13.4% had stable disease. The median time to progression was 5 mo and the median time until the start of a consecutive antineoplastic therapy was 8.5 mo. Of importance, a PSA decrease ≥30% after the first two cycles of 177Lu PSMA (1 cycle: p = 0.0003; 2 cycles: p = 0.004), absolute PSA after the first three cycles (1 cycle: p = 0.011; 2 cycles: p = 0.0005; 3 cycles: p = 0.002), and a PSA doubling time >6 mo (p = 0.009) were significantly correlated to treatment response. Furthermore, gamma-glutamyl transferase ≤31 U/L at the start of 177Lu PSMA therapy was correlated with 1.5 times higher risk of progression for patients without but not with visceral metastases (p = 0.046). CONCLUSIONS: 177Lu PSMA is an effective treatment option in mCRPC in the real-world setting. A PSA decrease ≥30% after the first two cycles is an early marker of response that can be easily implemented in clinical practice. PATIENT SUMMARY: 177Lu PSMA is a radioactive agent approved for treatment of advanced prostate cancer. We reviewed its use outside of clinical trials for patients treated at eight European centers. We found that 177Lu PSMA is an effective treatment option in real-world practice. A PSA (prostate-specific antigen) decrease of ≥30% after the first two therapy cycles is an early indicator of response to treatment and can be used in personalizing treatments for patients.

• MeSH
• antigeny povrchové metabolismus   MeSH
• glutamátkarboxypeptidasa II metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• ligandy MeSH
• lutecium * terapeutické užití   MeSH
• metastázy nádorů MeSH
• nádorové biomarkery krev   MeSH
• nádory prostaty rezistentní na kastraci * patologie   radioterapie   farmakoterapie   MeSH
• prostatický specifický antigen krev   MeSH
• radionuklidy terapeutické užití   MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři 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
• pozorovací studie MeSH
• Geografické názvy
• Evropa MeSH

Asi u čtvrtiny mužů s metastatickým kastračně rezistentním karcinomem prostaty (mCRPC) můžeme nalézt mutaci v některém z genů, které se účastní oprav DNA pomocí homologní rekombinace. Proteinovou skupinu poly-adenozindifosfát-ribózo-polymeráz (PARP) můžeme zablokovat pomocí tzv. PARP inhibitorů a opravy DNA tak neproběhnou. Prvním PARP inhibitorem, schváleným pro léčbu mCRPC progredujícího po léčbě abirateronem nebo enzalutamidem, je olaparib. Navíc v kombinaci s abirateronem jej můžeme použít již v první linii, kdy mCRPC progreduje na standardní hormonální léčbě.

About a quarter of men with metastatic castration-resistant prostate cancer (mCRPC) have a mutation in one of the genes involved in DNA repair through homologous recombination. The protein group poly (ADP-ribose) polymerase (PARP) can be blocked using so-called PARP inhibitors and DNA repair will not be done. The first PARP inhibitor approved for the treatment of mCRPC progressing after treatment with abiraterone or enzalutamide is olaparib. In addition, in combination with abiraterone, we can use it already in the first line, when mCRPC progresses on standard hormonal treatment.

• Klíčová slova
• olaparib,
• MeSH
• abirateron aplikace a dávkování   MeSH
• doba přežití bez progrese choroby MeSH
• klinická studie jako téma MeSH
• kombinovaná farmakoterapie metody   MeSH
• lidé MeSH
• metastázy nádorů farmakoterapie   MeSH
• nádory prostaty rezistentní na kastraci farmakoterapie   genetika   komplikace   MeSH
• nádory prostaty * farmakoterapie   genetika   komplikace   MeSH
• PARP inhibitory * aplikace a dávkování   farmakologie   MeSH
• protinádorové látky aplikace a dávkování   MeSH
• statistika jako téma MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH