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.

• Klíčová slova
• Apalutamide, Metastatic castration-sensitive prostate cancer, Prostate-specific antigen, Radiographic progression,
• Publikační typ
• časopisecké články MeSH

Management of non-metastatic castration-resistant prostate cancer (nmCRPC) has undergone a paradigm shift with next-generation androgen receptor inhibitors. However, direct comparative data are not available to inform treatment decisions and/or guideline recommendations. Therefore, we performed network meta-analysis to indirectly compare the efficacy and safety of currently available treatments. Multiple databases were searched for articles published before June 2020. Studies that compared overall and/or metastasis-free and/or prostate-specific antigen (PSA) progression-free survival (OS/MFS/PSA-PFS) and/or adverse events (AEs) in nmCRPC patients were considered eligible. Three studies (n = 4117) met our eligibility criteria. Formal network meta-analyses were conducted. For MFS, apalutamide, darolutamide, and enzalutamide were significantly more effective than placebo, and apalutamide emerged as the best option (P score: 0.8809). Apalutamide [hazard ratio (HR): 0.85, 95% credible interval (CrI): 0.77-0.94] and enzalutamide (HR: 0.86, 95% CrI: 0.78-0.95) were both significantly more effective than darolutamide. For PSA-PFS, all three agents were statistically superior to placebo, and apalutamide emerged as the likely preferred option (P score: 1.000). Apalutamide (HR: 0.71, 95% CrI: 0.69-0.74) and enzalutamide (HR: 0.76, 95% CrI: 0.74-0.79) were both significantly more effective than darolutamide. For AEs (including all AEs, grade 3 or grade 4 AEs, grade 5 AEs, and discontinuation rates), darolutamide was the likely best option. Apalutamide and enzalutamide appear to be more efficacious agents for therapy of nmCRPC, while darolutamide appears to have the most favorable tolerability profile. These findings may facilitate individualized treatment strategies and inform future direct comparative trials.

• Klíčová slova
• Apalutamide, Darolutamide, Enzalutamide, Network meta-analysis, Non-metastatic castration-resistant prostate cancer,
• MeSH
• antagonisté androgenních receptorů terapeutické užití   MeSH
• antitumorózní látky terapeutické užití   MeSH
• benzamidy MeSH
• doba přežití bez progrese choroby MeSH
• fenylthiohydantoin analogy a deriváty   terapeutické užití   MeSH
• kalikreiny metabolismus   MeSH
• lidé MeSH
• nádory prostaty rezistentní na kastraci farmakoterapie   mortalita   patologie   MeSH
• nitrily MeSH
• proporcionální rizikové modely MeSH
• prostatický specifický antigen metabolismus   MeSH
• pyrazoly terapeutické užití   MeSH
• síťová metaanalýza MeSH
• thiohydantoiny terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• systematický přehled MeSH
• Názvy látek
• antagonisté androgenních receptorů MeSH
• antitumorózní látky MeSH
• apalutamide MeSH Prohlížeč
• benzamidy MeSH
• darolutamide MeSH Prohlížeč
• enzalutamide MeSH Prohlížeč
• fenylthiohydantoin MeSH
• kalikreiny MeSH
• KLK3 protein, human MeSH Prohlížeč
• nitrily MeSH
• prostatický specifický antigen MeSH
• pyrazoly MeSH
• thiohydantoiny MeSH

BACKGROUND: The most recent overall survival (OS) and adverse event (AE) data have not been compared for the three guideline-recommended high-risk non-metastatic castration-resistant prostate cancer (nmCRPC) treatment alternatives. METHODS: We performed a systematic review and network meta-analysis focusing on OS and AE according to the most recent apalutamide, enzalutamide, and darolutamide reports. We systematically examined and compared apalutamide vs. enzalutamide vs. darolutamide efficacy and toxicity, relative to ADT according to PRISMA. We relied on PubMed search for most recent reports addressing prospective randomized trials with proven predefined OS benefit, relative to ADT: SPARTAN, PROSPER, and ARAMIS. OS represented the primary outcome and AEs represented secondary outcomes. RESULTS: Overall, data originated from 4117 observations made within the three trials that were analyzed. Regarding OS benefit relative to ADT, darolutamide ranked first, followed by enzalutamide and apalutamide, in that order. In the subgroup of PSA-doubling time (PSA-DT) ≤ 6 months patients, enzalutamide ranked first, followed by darolutamide and apalutamide in that order. Conversely, in the subgroup of PSA-DT 6-10 months patients, darolutamide ranked first, followed by apalutamide and enzalutamide, in that order. Regarding grade 3+ AEs, darolutamide was most favorable, followed by enzalutamide and apalutamide, in that order. CONCLUSION: The current network meta-analysis suggests the highest OS efficacy and lowest grade 3+ toxicity for darolutamide. However, in the PSA-DT ≤ 6 months subgroup, the highest efficacy was recorded for enzalutamide. It is noteworthy that study design, study population, and follow-up duration represent some of the potentially critical differences that distinguish between the three studies and remained statistically unaccounted for using the network meta-analysis methodology. Those differences should be strongly considered in the interpretation of the current and any network meta-analyses.

• MeSH
• benzamidy MeSH
• fenylthiohydantoin MeSH
• lidé MeSH
• nádory prostaty rezistentní na kastraci * farmakoterapie   patologie   MeSH
• nitrily MeSH
• prospektivní studie MeSH
• prostatický specifický antigen MeSH
• pyrazoly MeSH
• síťová metaanalýza MeSH
• thiohydantoiny MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• systematický přehled MeSH
• Názvy látek
• apalutamide MeSH Prohlížeč
• benzamidy MeSH
• darolutamide MeSH Prohlížeč
• enzalutamide MeSH Prohlížeč
• fenylthiohydantoin MeSH
• nitrily MeSH
• prostatický specifický antigen MeSH
• pyrazoly MeSH
• thiohydantoiny MeSH

• Publikační typ
• tisková chyba MeSH

CONTEXT: Novel prospective randomized controlled observations addressing combination therapy in metastatic hormone-sensitive prostate cancer (mHSPC) have demonstrated promising overall survival (OS) outcomes. OBJECTIVE: To compare these novel findings and systematically review and address them within formal network meta-analyses (NMAs) that include observations from other prospective randomized controlled trials (RCTs). EVIDENCE ACQUISITION: First, we focused on abiraterone, enzalutamide, apalutamide, and docetaxel effects on OS in mHSPC using the PRISMA methodology. PubMed and abstracts identified prospective RCTs in first-line mHSPC. Second, we focused on mature studies that reached median OS and tested OS between abiraterone and docetaxel with tumor burden stratification. EVIDENCE SYNTHESIS: The first part included seven studies (n = 6639) and the second part, five studies (n = 4462). In the first part, abiraterone ranked first for high-volume mHSPC. Conversely, enzalutamide ranked first for low-volume mHSPC. In the second part, abiraterone treatment in high-volume mHSPC resulted in median OS of 50.1 mo and exceeded that with docetaxel (45.9 mo) and ADT alone (34.0 mo). Docetaxel treatment in low volume mHSPC resulted in median OS of 69.5 mo versus 67.7 mo with ADT alone. CONCLUSIONS: In conventional NMA that relied on conventional hazard ratios, differences were identified with respect to the relative efficacy of the combination therapies examined; abiraterone dominated the alternatives in high-volume mHSPC. In part two, which relied on trials for which median OS is available, comparison of abiraterone versus docetaxel revealed a 4-mo difference in OS in high-volume mHSPC. Conventional NMA may have overestimated the importance of treatment efficacy instead of focusing on median OS duration, which might represent a more important clinical endpoint. PATIENT SUMMARY: We reviewed studies on hormonal treatments and chemotherapy used for prostate cancer that has spread outside the prostate gland (metastatic prostate cancer, mPC). We found that the best overall survival was with the hormone agents abiraterone in high-volume mPC and enzalutamide in low-volume mPC. In comparison to the chemotherapy drug docetaxel, median overall survival with abiraterone was 4 months longer among patients with mPC.

• Klíčová slova
• Abiraterone, Androgen deprivation therapy, Apalutamide, Docetaxel, Enzalutamide, High volume, Low volume, Metastatic burden,
• MeSH
• antagonisté androgenů terapeutické užití   MeSH
• docetaxel terapeutické užití   MeSH
• hormony terapeutické užití   MeSH
• lidé MeSH
• nádory prostaty * patologie   MeSH
• síťová metaanalýza MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• přehledy MeSH
• systematický přehled MeSH
• Názvy látek
• antagonisté androgenů MeSH
• docetaxel MeSH
• hormony MeSH

BACKGROUND: Non-metastatic castration-refractory prostate cancer (nmCRPC) is defined by increasing serum prostate specific antigen (PSA) levels despite androgen deprivation therapy in the absence of metastases on standard imaging methods including CT of the chest, abdomen and pelvis, and bone scan. Patients with nmCRPC and short PSA doubling time (PSAdt) are at high risk of developing early metastatic disease. OBJECTIVES: The objective of this review is to summarize current data on the treatment of nmCRPC. The current data support the efficacy of three novel androgen receptor targeted agents (ARTA), darolutamide, apalutamide and enzalutamide. CONCLUSIONS: The design and eligibility criteria of the three key studies with darolutamide, apalutamide and enzalutamide were similar. Patients were required to have a PSAdt.

• Klíčová slova
• androgen antagonists, antineoplastic agents, castration-refractory prostate cancer, drug toxicity, survival,
• MeSH
• androgenní receptory chemie   MeSH
• antagonisté androgenů terapeutické užití   MeSH
• antitumorózní látky terapeutické užití   MeSH
• cílená molekulární terapie metody   MeSH
• lidé MeSH
• nádory prostaty rezistentní na kastraci farmakoterapie   metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• androgenní receptory MeSH
• antagonisté androgenů MeSH
• antitumorózní látky MeSH
• AR protein, human MeSH Prohlížeč

OBJECTIVES: To perform a systematic review and network meta-analysis to compare the efficacy and safety of currently available treatments for the management of metastatic hormone-sensitive prostate cancer (mHSPC), as there has been a paradigm shift with the use of next-generation androgen receptor inhibitors (ARIs) and docetaxel. METHODS: Multiple databases were searched for articles published before May 2020 according to the Preferred Reporting Items for Systematic Review and Meta-analysis extension statement for network meta-analysis. Studies comparing overall/progression-free survival (OS/PFS) and/or adverse events (AEs) in patients with mHSPC were eligible. RESULTS: Nine studies (N = 9960) were selected, and formal network meta-analyses were conducted. Abiraterone (hazard ratio [HR] 0.83, 95% credible interval [CrI] 0.76-0.90), docetaxel (HR 0.90, 95% CrI 0.82-0.98), and enzalutamide (HR 0.85, 95% CrI 0.73-0.99) were associated with significantly better OS than androgen-deprivation therapy (ADT), and abiraterone emerged as the best option. Abiraterone (HR 0.71, 95% CrI 0.67-0.76), apalutamide (HR 0.73, 95% CrI 0.65-0.81), docetaxel (HR 0.84, 95% CrI 0.78-0.90), and enzalutamide (HR 0.67, 95% CrI 0.63-0.71) were associated with significantly better PFS than ADT, and enzalutamide emerged as the best option. Abiraterone (HR 0.85, 95% CrI 0.78-0.93), apalutamide (HR 0.87, 95% CrI 0.77-0.98), and enzalutamide (HR 0.80, 95% CrI 0.73-0.88) were significantly more effective than docetaxel. Regarding AEs, apalutamide was the likely best option among the three ARIs. In patients with low-volume mHSPC, enzalutamide was the best option in terms of OS and PFS. CONCLUSIONS: All three ARIs are effective therapies for mHSPC; apalutamide was the best tolerated. All three seemed more effective than docetaxel. These findings may facilitate individualised treatment strategies and inform future comparative trials.

• Klíčová slova
• #PCSM, #ProstateCancer, androgen receptor inhibitors, docetaxel, metastatic hormone-sensitive prostate cancer, network meta-analysis,
• MeSH
• antagonisté androgenních receptorů MeSH
• antagonisté androgenů * škodlivé účinky   MeSH
• docetaxel terapeutické užití   MeSH
• hormony MeSH
• lidé MeSH
• nádory prostaty * patologie   MeSH
• síťová metaanalýza MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• přehledy MeSH
• systematický přehled MeSH
• Názvy látek
• antagonisté androgenních receptorů MeSH
• antagonisté androgenů * MeSH
• docetaxel MeSH
• hormony MeSH

Novel androgen deprivation agents delay metastasis in non-metastatic, castration-resistant, prostate cancer (nmCRPC). The recent regulatory guidance: considerations for metastasis-free survival endpoint in clinical trials, opens new opportunities in cell biology, medicinal chemistry and advanced imaging. Past failures are the likely result of equating tumour shrinkage to efficacy, rather than inhibition of tumour spread. In the future, the selection of anti-metastasis drug candidates will probably be based on anti-migratory rather than anti-proliferative potential. Oligometastatic cancer coupled with advanced imaging can serve as a clinical proof-of-concept model.

• MeSH
• antagonisté androgenů terapeutické užití   MeSH
• benzamidy MeSH
• chemorezistence genetika   MeSH
• doba přežití bez progrese choroby MeSH
• fenylthiohydantoin analogy a deriváty   terapeutické užití   MeSH
• lidé MeSH
• metastázy nádorů diagnostické zobrazování   prevence a kontrola   MeSH
• nádory prostaty rezistentní na kastraci krev   diagnostické zobrazování   farmakoterapie   patologie   MeSH
• nitrily MeSH
• pohyb buněk účinky léků   MeSH
• progrese nemoci MeSH
• proliferace buněk účinky léků   MeSH
• prostatický specifický antigen krev   MeSH
• pyrazoly terapeutické užití   MeSH
• směrnice pro lékařskou praxi jako téma MeSH
• testosteron krev   MeSH
• thiohydantoiny terapeutické užití   MeSH
• tumor burden účinky léků   MeSH
• Úřad Spojených států pro potraviny a léky MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH
• úvodníky MeSH
• Geografické názvy
• Spojené státy americké MeSH
• Názvy látek
• antagonisté androgenů MeSH
• apalutamide MeSH Prohlížeč
• benzamidy MeSH
• darolutamide MeSH Prohlížeč
• enzalutamide MeSH Prohlížeč
• fenylthiohydantoin MeSH
• nitrily MeSH
• prostatický specifický antigen MeSH
• pyrazoly MeSH
• testosteron MeSH
• thiohydantoiny MeSH

INTRODUCTION: The management of non-metastatic castration-resistant prostate cancer (nmCRPC) has undergone a paradigm shift with the development of androgen receptor axis-targeted (ARAT) agents. The updated results with final overall survival (OS) data of the phase III PROSPER, SPARTAN, and ARAMIS trials have recently been reported. Therefore, we performed an updated meta-analysis and network meta-analysis to indirectly compare the efficacy and safety of currently available treatments. EVIDENCE ACQUISITION: Multiple databases were searched for articles published before January 2021. Studies that compared OS and adverse events (AEs) in patients with nmCRPC were considered eligible. EVIDENCE SYNTHESIS: Three studies (N.=4117) met our eligibility criteria. Formal network meta-analyses were conducted. ARAT agent is associated with significantly longer OS compared to placebo (pooled hazard ratio [HR]: 0.74, 95% confidence interval [CI]: 0.65-0.83, P<0.001), with similar results shown for patients with both N1 and N0 disease (pooled HR 0.61 and pooled HR 0.76, respectively). In the network meta-analysis, apalutamide, darolutamide, and enzalutamide were more effective than placebo, with similar efficacies in terms of OS. For AEs (including any AEs, grade 3 or grade 4 AEs, grade 5 AEs, serious AEs, and AEs leading to treatment discontinuation), darolutamide was shown to be likely well tolerated. Quality of Life was preserved in treatment arms irrespective of the drug. CONCLUSIONS: All three ARAT agents are efficacious options for the treatment of nmCRPC, whereas darolutamide appears to have the most favorable tolerability profile. These findings may facilitate individualized treatment strategies and inform future direct comparative trials.

• MeSH
• antagonisté androgenních receptorů * škodlivé účinky   MeSH
• antitumorózní látky * škodlivé účinky   MeSH
• kvalita života MeSH
• lidé MeSH
• nádory prostaty rezistentní na kastraci * farmakoterapie   patologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• Názvy látek
• antagonisté androgenních receptorů * MeSH
• antitumorózní látky * MeSH

CONTEXT: Recent randomized controlled trials (RCTs) examined the role of adding androgen receptor signaling inhibitors (ARSIs), including abiraterone acetate (ABI), apalutamide, darolutamide (DAR), and enzalutamide (ENZ), to docetaxel (DOC) and androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). OBJECTIVE: To analyze the oncologic benefit of triplet combination therapies using ARSI + DOC + ADT, and comparing them with available treatment regimens in patients with mHSPC. EVIDENCE ACQUISITION: Three databases and meetings abstracts were queried in April 2022 for RCTs analyzing patients treated with first-line combination systemic therapy for mHSPC. The primary interests of measure were overall survival (OS) and progression-free survival (PFS). Subgroup analyses were conducted to assess the differential outcomes in patients with low- and high-volume disease as well as de novo and metachronous metastasis. EVIDENCE SYNTHESIS: Overall, 11 RCTs were included for meta-analyses and network meta-analyses (NMAs). We found that the triplet combinations outperformed DOC + ADT in terms of OS (pooled hazard ratio [HR]: 0.74, 95% confidence interval [CI]: 0.65-0.84) and PFS (pooled HR: 0.49, 95% CI: 0.42-0.58). There was no statistically significant difference between patients with low- and high-volume disease in terms of an OS benefit from adding an ARSI to DOC +ADT (both HR: 0.79; p = 1). Based on NMAs, triplet therapy also outperformed ARSI + ADT in terms of OS (DAR + DOC + ADT: pooled HR: 0.74, 95% CI: 0.55-0.99) and PFS (ABI + DOC + ADT: HR: 0.68, 95% CI: 0.51-0.91, and ENZ + DOC + ADT: HR: 0.70, 95% CI: 0.53-0.93). An analysis of treatment ranking among de novo mHSPC patients showed that triplet therapy had the highest likelihood of improved OS in patients with high-volume disease; however, doublet therapy using ARSI + ADT had the highest likelihood of improved OS in patients with low-volume disease. CONCLUSIONS: We found that the triplet combination therapy improves survival endpoints in mHSPC patients compared with currently available doublet treatment regimens. Our findings need to be confirmed in further head-to-head trials with longer follow-up and among various patient populations. PATIENT SUMMARY: Our study suggests that triplet therapy with androgen receptor signaling inhibitor, docetaxel, androgen deprivation therapy prolongs survival in patients with metastatic hormone-sensitive prostate cancer compared with the current standard doublet therapy.

• Klíčová slova
• Androgen receptor signaling inhibitor, Docetaxel, Metastatic hormone-sensitive prostate cancer,
• MeSH
• androgenní receptory MeSH
• androgeny terapeutické užití   MeSH
• antagonisté androgenů * škodlivé účinky   MeSH
• docetaxel terapeutické užití   MeSH
• lidé MeSH
• nádory prostaty * patologie   MeSH
• protokoly antitumorózní kombinované chemoterapie škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• systematický přehled MeSH
• Názvy látek
• androgenní receptory MeSH
• androgeny MeSH
• antagonisté androgenů * MeSH
• docetaxel MeSH
• enzalutamide MeSH Prohlížeč