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1.
Cancer Med ; 12(15): 16490-16501, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37325888

RESUMO

BACKGROUND: Abiraterone and enzalutamide are castration-resistant prostate cancer (CRPC) therapies with potentially distinct associations with mental health symptoms given their differing antiandrogen targets. METHODS: We used national Veterans Health Administration data to identify patients with CRPC who received first-line abiraterone or enzalutamide from 2010 to 2017. Using Poisson regression, we compared outpatient mental health encounters per 100 patient-months on drug between the abiraterone and enzalutamide cohorts adjusting for patient factors (e.g., age). We compared mental health encounters in the year before versus after starting therapy using the McNemar test. RESULTS: We identified 2902 CRPC patients who received abiraterone (n = 1992) or enzalutamide (n = 910). We found no difference in outpatient mental health encounters between the two groups (adjusted incident rate ratio [aIRR] 1.04, 95% confidence interval [CI] 0.95-1.15). However, men with preexisting mental health diagnoses received 81.3% of the outpatient mental health encounters and had higher rates of these encounters with enzalutamide (aIRR 1.21, 95% CI 1.09-1.34). Among patients with ≥1 year of enrollment before and after starting abiraterone (n = 1139) or enzalutamide (n = 446), there was no difference in mental health care utilization before versus after starting treatment (17.0% of patients vs. 17.6%, p = 0.60, abiraterone; 16.4% vs. 18.4%, p = 0.26, enzalutamide). CONCLUSION: We found no overall differences in mental health care utilization between CRPC patients who received first-line abiraterone versus enzalutamide. However, men with preexisting mental health diagnoses received the majority of mental health care and had more mental health visits with enzalutamide.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/epidemiologia , Androstenos/uso terapêutico , Nitrilas/uso terapêutico , Aceitação pelo Paciente de Cuidados de Saúde , Resultado do Tratamento
2.
Prostate ; 83(13): 1279-1284, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37337669

RESUMO

INTRODUCTION: Abiraterone and concurrent androgen deprivation therapy (ADT) are used in the treatment of patients with metastatic castration-resistant prostate cancer. Recently, it has been suggested that the use of abiraterone alone (without ADT) may have comparable efficacy to abiraterone with ongoing ADT. Here, we sought to assess the impact of ADT cessation in patients beginning abiraterone for castration-resistant prostate cancer. METHODS: We identified 39 patients at our institution who received abiraterone alone (with discontinuation of ADT) between 2011 and 2022. We then procured a comparable group of 39 patients (matched by age, Gleason score, and prostate-specific antigen [PSA] level) who received abiraterone with ongoing ADT during the same period. We assessed and compared clinical outcomes in the two groups (abiraterone-alone vs. abiraterone-ADT) with respect to PSA response rates, PSA progression-free survival, and overall survival. Results were adjusted using Cox proportional-hazards multivariable models. RESULTS: The median PSA before treatment initiation was 12.7 (range: 0.2-199) ng/mL in the abiraterone-alone group and 15.5 (range: 0.6-212) ng/mL in the abiraterone-ADT group. Use of abiraterone alone adequately suppressed testosterone levels in 35/37 (94.6%) patients. Patients receiving abiraterone alone had a median PSA reduction of 80.2% versus 79.5% in patients receiving abiraterone plus ADT. The median PSA progression-free survival in patients receiving abiraterone alone was 27.4 versus 25.8 months in patients receiving abiraterone plus ADT (hazard ratio [HR] 1.10; 95% confidence interval [CI] 0.65-1.71; p = 0.82). In addition, abiraterone alone was associated with an overall survival of 3.6 versus 3.1 years in patients receiving abiraterone plus ADT (HR 0.90; 95% CI 0.50-1.62; p = 0.72). There were no differences in PFS or OS between groups after performing Cox multivariable regression analyses. CONCLUSION: Use of abiraterone alone was associated with comparable clinical outcomes to patients who received abiraterone together with ADT. Further prospective studies are warranted to evaluate the impact of abiraterone alone on treatment outcomes and cost savings.


Assuntos
Antagonistas de Androgênios , Androstenos , Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Androstenos/uso terapêutico , Metástase Neoplásica/patologia , Estudos Retrospectivos , Estudos de Casos e Controles , Intervalo Livre de Progressão , Antagonistas de Androgênios/uso terapêutico , Resultado do Tratamento
4.
J Occup Environ Med ; 65(7): e491-e495, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-37130820

RESUMO

OBJECTIVE: The aim of the study is to examine changes in work productivity and daily activity impairment among women by starting ethinylestradiol (EE)/drospirenone (DRSP) for perimenstrual symptoms. METHODS: Participants were women who were newly prescribed EE/DRSP at 25 gynecological clinics in Japan. Eligible participants recorded daily intake of EE/DRSP and the Work Productivity Activity Impairment Questionnaire General Health every 2 weeks for 3 months by smartphone app. A linear mixed-effects model was used to see changes in work productivity impairment and activity impairment relative to baseline. RESULTS: A total of 222 participants were eligible. Work productivity impairment recovered by 20.0% (95% confidence interval, 14.1%-26.0%) at 1 m and maintained for 2 months. Activity impairment recovered by 20.1% (95% confidence interval, 15.5%-24.7%) at 1 m and thereafter. CONCLUSIONS: Improvements in work productivity and daily activities were observed at 1 m after EE/DRSP initiation, with a sustained effect thereafter.


Assuntos
Linestrenol , Ciclo Menstrual , Distúrbios Menstruais , Desempenho Profissional , Estudos Prospectivos , Smartphone , Humanos , Masculino , Feminino , Adolescente , Adulto Jovem , Adulto , Androstenos/uso terapêutico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Japão , Atividades Cotidianas , Linestrenol/uso terapêutico , Distúrbios Menstruais/tratamento farmacológico , Ciclo Menstrual/efeitos dos fármacos , Resultado do Tratamento
6.
Nat Commun ; 14(1): 1968, 2023 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-37031196

RESUMO

Response to androgen receptor signaling inhibitors (ARSI) varies widely in metastatic castration resistant prostate cancer (mCRPC). To improve treatment guidance, biomarkers are needed. We use whole-genomics (WGS; n = 155) with matching whole-transcriptomics (WTS; n = 113) from biopsies of ARSI-treated mCRPC patients for unbiased discovery of biomarkers and development of machine learning-based prediction models. Tumor mutational burden (q < 0.001), structural variants (q < 0.05), tandem duplications (q < 0.05) and deletions (q < 0.05) are enriched in poor responders, coupled with distinct transcriptomic expression profiles. Validating various classification models predicting treatment duration with ARSI on our internal and external mCRPC cohort reveals two best-performing models, based on the combination of prior treatment information with either the four combined enriched genomic markers or with overall transcriptomic profiles. In conclusion, predictive models combining genomic, transcriptomic, and clinical data can predict response to ARSI in mCRPC patients and, with additional optimization and prospective validation, could improve treatment guidance.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Androstenos/uso terapêutico , Feniltioidantoína/uso terapêutico , Nitrilas/uso terapêutico , Biomarcadores Tumorais/genética , Resultado do Tratamento
7.
PLoS One ; 18(3): e0282646, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36893142

RESUMO

Patients with metastatic castration-resistant prostate cancer (mCRPC) are divided into three groups based on their response to Abiraterone treatment: best responder, responder, and non-responder. In the latter two groups, successful outcomes may not be achieved due to the development of drug-resistant cells in the tumor environment during treatment. To overcome this challenge, a secondary drug can be used to control the population of drug-resistant cells, potentially leading to a longer period of disease inhibition. This paper proposes using a combination of Docetaxel and Abiraterone in some polytherapy methods to control both the overall cancer cell population and the drug-resistant subpopulation. To investigate the competition and evolution of mCRPC cancer phenotypes, as in previous studies, the Evolutionary Game Theory (EGT) has been used as a mathematical modeling of evolutionary biology concepts.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Docetaxel/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Taxoides/farmacologia , Taxoides/uso terapêutico , Androstenos/farmacologia , Androstenos/uso terapêutico , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos Retrospectivos , Acetato de Abiraterona
8.
Prostate ; 83(6): 524-533, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36604824

RESUMO

BACKGROUND: Inactivating alterations in SPOP frequently occur in prostate cancer and promote increased dependency on androgen receptor (AR)-mediated oncogenic signaling. The presence of SPOP mutation (SPOP-mutant [SPOP-mut]) may therefore impact therapeutic outcomes with AR-directed therapies and docetaxel in metastatic castration-resistant (mCRPC). METHODS: This was a retrospective study of mCRPC patients treated at an urban academic hospital (n = 103). Patients underwent tumor DNA sequencing to determine SPOP mutational status (SPOP-mut). Outcomes measured were overall survival (OS) from diagnosis and treatment with second-generation AR signaling inhibitor (ARSI) or docetaxel and time to PSA progression (prostate-specific antigen-progression-free survival [PSA-PFS]) compared by SPOP status using Kaplan-Meier curves and log-rank test. The univariable and multivariable Cox proportional hazard model evaluated the association of SPOP mutation and outcomes adjusted for clinicopathologic features. RESULTS: SPOP-mut was associated with longer PSA-PFS in mCRPC (median 1.79 vs. 0.84 years; p = 0.06) and multivariate analysis (hazard ratio [HR] = 0.37; 95% confidence interval [CI]: 0.17-0.84; p = 0.02). SPOP-mut demonstrated a higher median PSA decline compared to SPOP wild-type (median decline 100% vs. 92%, p = 0.02). SPOP-mut was not associated with OS from the start of ARSI or docetaxel (median OS not reached vs. 2.0 years) or PSA-PFS on docetaxel (median PSA-PFS 0.4 vs. 0.5 years) in mCRPC. The majority of SPOP mutations were identified in African American (AA) patients (69.2%) compared to Caucasian patients (30.8%). Race-associated multivariate analysis revealed no significant differences in OS from the start of ARSI or the start of docetaxel and no differences in ARSI or docetaxel PSA-PFS between AA and Caucasian patients. Molecular profiling demonstrated that AA patients had a higher frequency of SPOP mutations and greater heterogeneity of SPOP variants within the coding sequence. Analysis of concurrent genomic alterations revealed that SPOP mutations co-occur with APC mutations (p = 0.001) and alterations in the Wnt pathway (p = 0.017). CONCLUSIONS: Inactivating mutations in SPOP are associated with better response to ARSI treatment in mCRPC overall. Additional analysis with a larger cohort is needed to evaluate the association of SPOP status and outcomes with docetaxel. Race-associated clinical outcomes and molecular features were observed, suggesting the benefit of biomarker-directed therapy selection for individualized patient subsets in guiding treatment decisions for mCRPC patients.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Docetaxel/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Antígeno Prostático Específico/uso terapêutico , Resultado do Tratamento , Estudos Retrospectivos , Androstenos/uso terapêutico , Nitrilas/uso terapêutico , Intervalo Livre de Doença
9.
Aging (Albany NY) ; 14(24): 9942-9950, 2022 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-36541904

RESUMO

Abiraterone acetate has exhibited impressive results in improving progression-free survival of patients with metastatic castration-resistant prostate cancer. However, many patients may develop abiraterone resistance with a variable duration of response. Hence, identifying a remedy to overcome abiraterone resistance is critical for patients with castration-resistant prostate cancer. In this study, we aim to explore the potential of Qi Ling decoction (QLD), a traditional Chinese medicine, in attenuating abiraterone resistance in prostate cancer. Cell viability and apoptosis were respectively measured by Cell Counting Kit-8 (CCK-8) assay and flow cytometry. The protein levels were assessed by Western blotting assay. Autophagosome formation was quantified by counting LC3 puncta. We found that QLD was capable of promoting abiraterone-induced apoptosis and cell death of PC3-AbiR and DU145-AbiR cells in vitro. A combination of QLD and abiraterone yielded a better tumor inhibition effect than QLD alone and abiraterone alone. Further investigation revealed that QLD restored the abiraterone sensitivity of PC3-AbiR and DU145-AbiR cells through modulating autophagy. These findings suggest that QLD might serve as a potential remedy to enhance the therapeutical effect of abiraterone for patients with castration-resistant prostate cancer.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Qi , Androstenos/farmacologia , Androstenos/uso terapêutico , Autofagia
10.
JAMA Netw Open ; 5(9): e2231475, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-36178694

RESUMO

This cross-sectional study evaluates the association of generic competition and changes in product coverage and cost-sharing by using Medicare data and estimated out-of-pocket costs for the oral specialty drug abiraterone.


Assuntos
Gastos em Saúde , Medicare Part D , Idoso , Androstenos/uso terapêutico , Custo Compartilhado de Seguro , Humanos , Estados Unidos
11.
Contraception ; 116: 37-43, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35921870

RESUMO

OBJECTIVE: To evaluate overall and subgroup efficacy of an estetrol (E4) 15 mg drospirenone (DRSP) 3 mg oral contraceptive in a 24/4-day regimen. STUDY DESIGN: We pooled efficacy outcomes from 2 pivotal phase 3 contraceptive trials with E4/DRSP conducted in the United States/Canada and Europe/Russia. We assessed Pearl Index (PI; pregnancies per 100 participant-years) and 13-cycle life-table pregnancy rates in at-risk cycles (confirmed intercourse and no other contraceptive use) among participants 16 to 35 years. We calculated PI by age and further subcategorization (contraceptive history and body mass index [BMI]). We performed multivariable analysis using Cox regression to assess impact of potential confounding factors. RESULTS: Analyses included 3027 participants, of whom 451 (14.9%) had a BMI ≥30 kg/m2. The pooled PI was 1.52 (95% confidence interval 1.04-2.16) and the 13-cycle life-table pregnancy rate was 1.28% (0.83%-1.73%). We calculated unadjusted pooled PI in participants 16 to 25 years and 26 to 35 years of 1.61 (0.94-2.57) and 1.43 (0.78-2.40), respectively; in new starters and switchers of 1.88 (1.09-3.00) and 1.24 (0.68-2.08), respectively; and by BMI <25 kg/m2, 25 to 29.9 kg/m2, and ≥30 kg/m2 of 1.14 (0.64-1.88), 2.19 (1.05-4.03), and 2.27 (0.83-4.94), respectively. In multivariable analysis, we found associations of prior pregnancy (hazard ratio [HR] 3.61[1.56-8.38]), Black race (HR 4.61[1.97-10.80]), age 16 to 25 years (HR 2.37[1.09-5.15]) and compliance <99% of expected pills (HR 4.21[2.04-8.66]) with conception. CONCLUSION: E4/DRSP is an effective oral contraceptive overall and across subgroups stratified by age, contraceptive history, and BMI. Other than compliance, predictors of contraceptive failure are nonmodifiable. IMPLICATIONS STATEMENT: Pooled results from two phase 3 trials demonstrate high contraceptive efficacy of the novel estetrol-drospirenone oral contraceptive. Several non-modifiable risk factors, including prior pregnancy, race, and age, are associated with higher pregnancy risk. Additional research is needed to better understand predictors of combined oral contraceptive failure.


Assuntos
Estetrol , Humanos , Gravidez , Feminino , Estados Unidos , Adolescente , Adulto Jovem , Adulto , Estetrol/efeitos adversos , Androstenos/uso terapêutico , Anticoncepcionais Orais Combinados , Anticoncepção/métodos , Estrogênios
12.
Prostate ; 82(13): 1284-1292, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35747943

RESUMO

BACKGROUND: To investigate the prognostic value and potential therapeutic target of the baseline serum hormones in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone. METHODS: This retrospective study was performed in patients with mCRPC receiving abiraterone acetate (AA) from July 2016 to September 2020. Patients who had serum hormone tests within 2 weeks before AA treatment were included. Univariate analysis and Cox regression were performed to evaluate the correlation of sex hormones with progression-free survival (PFS) and overall survival (OS). Prolactin (PRL) expression in the clinical specimens was evaluated by immunohistochemistry. Bone metastases were quantified by automated Bone Scan Index (aBSI). RESULTS: The study included 61 patients with a median follow-up of 19.0 months. Patients with lower baseline PRL levels (median) responded better to AA than those with higher baseline PRL levels as indicated by prostate-specific antigen (PSA) reduction (PSA90, 66.7% vs. 25.8%, p = 0.001), PFS (19.6 vs. 7.9 months), and OS (52.8 vs. 19.2 months). Cox regression adjusted for clinical factors also confirmed that baseline PRL level was an independent predictive factor for PFS (hazard ratio = 1.096, p = 0.007). Prostatic PRL expression increased as the disease progressed. PRL expression was also detected in biopsy samples from bone metastasis but not in normal bone tissue, and the serum PRL levels were positively correlated with aBSIs (r = 0.28, p = 0.037). CONCLUSIONS: Serum PRL levels are predictive of response to AA in patients with mCRPC. Serum PRL levels are positively correlated with the volume of metastatic bone disease.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Acetato de Abiraterona/uso terapêutico , Androstenos/uso terapêutico , Humanos , Masculino , Prolactina/uso terapêutico , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos , Resultado do Tratamento
13.
Radiol Med ; 127(8): 912-918, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35763249

RESUMO

BACKGROUND: ARTO trial was designed to evaluate the difference in terms of outcomes between patients affected by oligo metastatic castrate resistant prostate cancer (mCRPC) treated with Abiraterone acetate and randomized to receive or not SBRT on all sites of disease. Here, we present a preliminary analysis conducted on patients enrolled at promoting institution. OBJECTIVE: To present a preliminary overview about population features, clinical outcomes, adverse events, quality of life and explorative translational research. DESIGN, SETTING, AND PARTICIPANTS: ARTO (NCT03449719) is a phase II trial including patients affected by oligo mCRPC, randomized to receive standard of care (GnRH agonist or antagonist plus abiraterone acetate 1000 mg and oral prednisone 10 mg daily) with or without SBRT on all metastatic sites of disease. All subjects have < 3 bone or nodal metastases. All patients are treated in I line mCRPC setting, no previous lines of treatment for mCRPC are allowed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Data about a mono-centric cohort of 42 patients enrolled are presented in the current analysis, with focus on baseline population features, PSA drop at 3 months, biochemical response, and quality of life outcomes. Descriptive statistics regarding translational research are also presented. RESULTS AND LIMITATION: Significant difference in terms of PSA drop at three months was not detected (p = 0.68). Biochemical response (PSA reduction > 50%) was reported in 73.7 versus 76.5% of patients in control vs SBRT arm, respectively (p = 0.84). All patients are alive. Progression occurred in 1 versus 0 patients in the control versus SBRT arm, respectively. After 3 months, an average decrease of 13 points in terms of Global Health Score was reported for the overall population. However, complete recovery was noticed at 6 months. Circulating tumor cells detection rate was 40%. CONCLUSIONS: SBRT + Abiraterone treatment was safe and well tolerated, non-significant trend in terms of PSA drop and biochemical response at 3 months was detected in SBRT arm. Interestingly, CTCs detection in this selected cohort of oligo-mCRPC was lower if compared to historical data of unselected mCRPC patients.


Assuntos
Androstenos , Quimiorradioterapia , Neoplasias de Próstata Resistentes à Castração , Radiocirurgia , Acetato de Abiraterona/uso terapêutico , Androstenos/uso terapêutico , Quimiorradioterapia/efeitos adversos , Protocolos de Ensaio Clínico como Assunto , Estudos de Coortes , Humanos , Masculino , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração/terapia , Qualidade de Vida , Resultado do Tratamento
14.
JAMA Netw Open ; 5(1): e2142093, 2022 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-34985518

RESUMO

Importance: Prospective evidence suggests abiraterone is associated with superior progression-free survival for African American men compared with non-Hispanic White men with metastatic castration-resistant prostate cancer (mCRPC). Objective: To investigate differences in outcomes with first-line abiraterone therapy between African American and non-Hispanic White men with mCRPC in a national real-world cohort. Design, Setting, and Participants: This retrospective cohort study used a nationwide electronic health record-derived database of 3808 men receiving first-line therapy for mCRPC between January 1, 2012, and December 31, 2018. Data analysis was performed between January 1, 2020, and June 1, 2021. Median follow-up was 13 months (IQR, 7-22 months). Propensity score-based inverse probability of treatment weighting was applied to reduce imbalance in measured confounders between patients receiving first-line abiraterone vs other first-line therapies. Deidentified patient data originated from a geographically diverse set of approximately 280 cancer clinics (approximately 800 sites of care) throughout the United States. Participants had newly diagnosed mCRPC and were receiving first-line systemic therapy during the study period. Exposures: Receipt of abiraterone for first-line therapy. Main Outcomes and Measures: Overall survival from start of first-line treatment. Stratified analyses investigated overall survival within each race group, with first-line enzalutamide as the comparator. Results: Among 3808 patients with mCRPC, there were 2615 non-Hispanic White men (68.7%; mean [SD] age at diagnosis, 74 [8] years) and 404 African American men (10.6%; mean [SD] age at diagnosis, 69 [9] years), and 1729 patients (45.4%) in the cohort received first-line abiraterone. Among patients receiving first-line abiraterone, African American men had higher median overall survival than non-Hispanic White men (23 months [IQR, 10-37 months] vs 17 months [IQR, 9-32 months], respectively; inverse probability of treatment weighting hazard ratio, 0.76; 95% CI, 0.60-0.98). A race-by-treatment interaction existed for first-line abiraterone vs first-line enzalutamide (hazard ratio for abiraterone vs enzalutamide: non-Hispanic White men, 1.21 [95% CI, 1.06-1.38]; African American men, 1.05 [95% CI, 0.74-1.50]; interaction P = .02). There was no overall survival difference between first-line abiraterone and first-line enzalutamide among African American patients (24 vs 24 months, respectively; inverse probability of treatment weighting hazard ratio, 1.05; 95% CI, 0.74-1.50). First-line abiraterone was associated with decreased median overall survival relative to first-line enzalutamide among non-Hispanic White patients (17 months [IQR, 9-32 months] vs 20 months [IQR, 10-36 months], respectively; inverse probability of treatment weighting hazard ratio, 1.21; 95% CI, 1.06-1.38). Conclusions and Relevance: In this cohort study of patients who received first-line systemic therapy for mCRPC, African American men who received abiraterone had improved overall survival compared with non-Hispanic White men. Future prospective studies should assess drivers of differential abiraterone outcomes in mCRPC between African American and non-Hispanic White men, including differences in genetic factors and socioeconomic status, to inform treatment strategies.


Assuntos
Androstenos/uso terapêutico , Antineoplásicos/uso terapêutico , Negro ou Afro-Americano/estatística & dados numéricos , Neoplasias de Próstata Resistentes à Castração , População Branca/estatística & dados numéricos , Idoso , Benzamidas/uso terapêutico , Humanos , Masculino , Nitrilas/uso terapêutico , Feniltioidantoína/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/epidemiologia , Neoplasias de Próstata Resistentes à Castração/mortalidade , Estudos Retrospectivos , Resultado do Tratamento
16.
Future Oncol ; 18(10): 1185-1198, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35034502

RESUMO

Cabozantinib inhibits multiple receptor tyrosine kinases, including the TAM kinase family, and may enhance response to immune checkpoint inhibitors. One cohort of the ongoing phase Ib COSMIC-021 study (NCT03170960) evaluating cabozantinib plus the PD-L1 inhibitor atezolizumab in men with metastatic castration-resistant prostate cancer (mCRPC) that has progressed in soft tissue on/after enzalutamide and/or abiraterone treatment for metastatic disease has shown promising efficacy. Here, we describe the rationale and design of a phase III trial of cabozantinib plus atezolizumab versus a second novel hormone therapy (NHT) in patients who have previously received an NHT for mCRPC, metastatic castration-sensitive PC or nonmetastatic CRPC and have measurable visceral disease and/or extrapelvic adenopathy - a population with a significant unmet need for treatment options. Trial Registration Clinical Trial Registration: NCT04446117 (ClinicalTrials.gov) Registered on 24 June 2020.


Assuntos
Adenocarcinoma/tratamento farmacológico , Anilidas/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Piridinas/uso terapêutico , Adenocarcinoma/patologia , Androstenos/uso terapêutico , Benzamidas/uso terapêutico , Humanos , Masculino , Metástase Neoplásica , Nitrilas/uso terapêutico , Feniltioidantoína/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores
17.
Prostate ; 82(5): 505-516, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35037287

RESUMO

INTRODUCTION: Castration-resistant prostate cancer (CRPC) remains dependent on androgen receptor (AR) signalling, which is largely driven by conversion of adrenal androgen precursors lasting after castration. Abiraterone, an inhibitor of the steroidogenic enzyme CYP17A1, has been demonstrated to reduce adrenal androgen synthesis and prolong CRPC patient survival. To study mechanisms of resistance to castration and abiraterone, we created coculture models using human prostate and adrenal tumours. MATERIALS AND METHODS: Castration-naïve and CRPC clones of VCaP were incubated with steroid substrates or cocultured with human adrenal cells (H295R) and treated with abiraterone or the antiandrogen enzalutamide. Male mice bearing VCaP xenografts with and without concurrent H295R xenografts were castrated and treated with placebo or abiraterone. Response was assessed by tumour growth and PSA release. Plasma and tumour steroid levels were assessed by LC/MS-MS. Quantitative polymerase chain reaction determined steroidogenic enzyme, nuclear receptor and AR target gene expression. RESULTS: In vitro, adrenal androgens induced castration-naïve and CRPC cell growth, while precursors steroids for de novo synthesis did not. In a coculture system, abiraterone blocked H295R-induced growth of VCaP cells. In vivo, H295R promoted castration-resistant VCaP growth. Abiraterone only inhibited VCaP growth or PSA production in the presence of H295R. Plasma steroid levels demonstrated CYP17A1 inhibition by abiraterone, whilst CRPC tumour tissue steroid levels showed no evidence of de novo intratumoural androgen production. Castration-resistant and abiraterone-resistant VCaP tumours had increased levels of AR, AR variants and glucocorticoid receptor (GR) resulting in equal AR target gene expression levels compared to noncastrate tumours. CONCLUSIONS: In our model, ligand-dependent AR-regulated regrowth of CRPC was predominantly supported via adrenal androgen precursor production while there was no evidence for intratumoural androgen synthesis. Abiraterone-resistant tumours relied on AR overexpression, expression of ligand-independent AR variants and GR signalling.


Assuntos
Androgênios , Neoplasias de Próstata Resistentes à Castração , Androgênios/metabolismo , Androstenos/farmacologia , Androstenos/uso terapêutico , Animais , Linhagem Celular Tumoral , Humanos , Ligantes , Masculino , Camundongos , Nitrilas/uso terapêutico , Orquiectomia , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Receptores de Glucocorticoides
19.
Prostate Cancer Prostatic Dis ; 25(3): 524-530, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-34732856

RESUMO

BACKGROUND: Black men are more likely to be diagnosed with aggressive prostate cancer (PC) and die from PC than white men. However, black men with metastatic castration-resistant PC (mCRPC) had longer overall survival (OS) than white men when treated with certain agents in clinical trials. We analyzed claims data from the Veterans Health Administration (VHA) database to evaluate OS in black and white men treated with enzalutamide or abiraterone (novel hormonal therapy [NHT]) for chemotherapy-naïve mCRPC. METHODS: Patients with mCRPC aged ≥18 years were identified in the VHA database by diagnosis codes, evidence of surgical/medical castration, and a prescription claim for enzalutamide or abiraterone after castration from April 2014-March 2017. Cox models assessed associations between race and OS. Unadjusted and multivariable analyses were performed on the entire population and subsets based on the type of therapy received (if any) after NHT. RESULTS: In total, 2910 patients were identified (787 black, mean 71.7 years; 2123 white, mean 74.0 years). Median follow-up was 19.0 and 18.7 months in blacks and whites, respectively. Black men had better survival versus white men: hazard ratios (95% CIs) were 0.89 (0.790-0.996; P = 0.044) and 0.67 (0.592-0.758; P < 0.0001) in the unadjusted and multivariable models, respectively. Statistically significantly longer OS was seen in black versus white men regardless of subsequent treatment, including no subsequent treatment. CONCLUSIONS: In the VHA, black men with chemotherapy-naïve mCRPC initiating NHT may have better outcomes than similarly treated white men.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Adolescente , Adulto , Androstenos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas , Humanos , Masculino , Nitrilas/uso terapêutico , Feniltioidantoína/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/patologia , Resultado do Tratamento
20.
Prostate ; 82(2): 269-275, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34822183

RESUMO

INTRODUCTION: Several studies in the Caucasian population have shown the benefit of using docetaxel, abiraterone, or enzalutamide for patients with metastatic prostate cancer at the castration-resistant stage (mCRPC). However, there are no strong data for men of African ancestry. The objective of this study was to estimate the overall and progression-free survival of patients according to these treatments at the mCRPC stage. PATIENTS AND METHODS: This was a monocentric retrospective study that consecutively included 211 men with mCRPC between June 1, 2009 and August 31, 2020. The primary end point was overall survival (OS). The secondary end point was progression-free survival. Kaplan-Meier survival and Cox proportional hazard analyses were performed. RESULTS: The present study included 180 patients for analyses. There was no difference in OS (log-rank test = 0.73), with a median follow-up of 20.7 months, regardless of the treatment administered in the first line. Men with mCRPC who received hormonotherapy (abiraterone or enzalutamide) showed better progression-free survival than those who received docetaxel (log-rank test = 0.004), with a particular interest for abiraterone hazard ratio (HR) = 0.51 (95% confidence interval: 0.39-0.67). The patient characteristics were similar, except for bone lesions, irrespective of the treatment administered in the first line. After univariate then multivariate analysis, only World Health Organization status and metastases at diagnosis were significantly associated with progression. CONCLUSION: Our results suggest the use of hormonotherapy (abiraterone or enzalutamide) with a tendency for abiraterone in first line for men with African ancestry at the mCRPC stage.


Assuntos
Androstenos/uso terapêutico , Benzamidas/uso terapêutico , População Negra/estatística & dados numéricos , Docetaxel/uso terapêutico , Metástase Neoplásica , Nitrilas/uso terapêutico , Feniltioidantoína/uso terapêutico , Neoplasias de Próstata Resistentes à Castração , Antineoplásicos/uso terapêutico , Guadalupe/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/diagnóstico , Metástase Neoplásica/terapia , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/etnologia , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/terapia , Estudos Retrospectivos , Resultado do Tratamento
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