RESUMO
Toward development of a precision medicine framework for metastatic, castration-resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals. Aberrations of AR, ETS genes, TP53, and PTEN were frequent (40%-60% of cases), with TP53 and AR alterations enriched in mCRPC compared to primary prostate cancer. We identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, ß-catenin, and ZBTB16/PLZF. Moreover, aberrations of BRCA2, BRCA1, and ATM were observed at substantially higher frequencies (19.3% overall) compared to those in primary prostate cancers. 89% of affected individuals harbored a clinically actionable aberration, including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. This cohort study provides clinically actionable information that could impact treatment decisions for these affected individuals.
Assuntos
Perfilação da Expressão Gênica/métodos , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos de Coortes , Humanos , Masculino , Mutação , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológicoRESUMO
Minimally invasive approaches to detect residual disease after surgery are needed to identify patients with cancer who are at risk for metastatic relapse. Circulating tumour DNA (ctDNA) holds promise as a biomarker for molecular residual disease and relapse1. We evaluated outcomes in 581 patients who had undergone surgery and were evaluable for ctDNA from a randomized phase III trial of adjuvant atezolizumab versus observation in operable urothelial cancer. This trial did not reach its efficacy end point in the intention-to-treat population. Here we show that ctDNA testing at the start of therapy (cycle 1 day 1) identified 214 (37%) patients who were positive for ctDNA and who had poor prognosis (observation arm hazard ratio = 6.3 (95% confidence interval: 4.45-8.92); P < 0.0001). Notably, patients who were positive for ctDNA had improved disease-free survival and overall survival in the atezolizumab arm versus the observation arm (disease-free survival hazard ratio = 0.58 (95% confidence interval: 0.43-0.79); P = 0.0024, overall survival hazard ratio = 0.59 (95% confidence interval: 0.41-0.86)). No difference in disease-free survival or overall survival between treatment arms was noted for patients who were negative for ctDNA. The rate of ctDNA clearance at week 6 was higher in the atezolizumab arm (18%) than in the observation arm (4%) (P = 0.0204). Transcriptomic analysis of tumours from patients who were positive for ctDNA revealed higher expression levels of cell-cycle and keratin genes. For patients who were positive for ctDNA and who were treated with atezolizumab, non-relapse was associated with immune response signatures and basal-squamous gene features, whereas relapse was associated with angiogenesis and fibroblast TGFß signatures. These data suggest that adjuvant atezolizumab may be associated with improved outcomes compared with observation in patients who are positive for ctDNA and who are at a high risk of relapse. These findings, if validated in other settings, would shift approaches to postoperative cancer care.
Assuntos
Adjuvantes Farmacêuticos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , DNA Tumoral Circulante/sangue , Imunoterapia , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/genética , Cuidados Pós-Operatórios , Prognóstico , Recidiva , Análise de Sobrevida , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/imunologiaRESUMO
BACKGROUND: Darolutamide is a potent androgen-receptor inhibitor that has been associated with increased overall survival among patients with nonmetastatic, castration-resistant prostate cancer. Whether a combination of darolutamide, androgen-deprivation therapy, and docetaxel would increase survival among patients with metastatic, hormone-sensitive prostate cancer is unknown. METHODS: In this international, phase 3 trial, we randomly assigned patients with metastatic, hormone-sensitive prostate cancer in a 1:1 ratio to receive darolutamide (at a dose of 600 mg [two 300-mg tablets] twice daily) or matching placebo, both in combination with androgen-deprivation therapy and docetaxel. The primary end point was overall survival. RESULTS: The primary analysis involved 1306 patients (651 in the darolutamide group and 655 in the placebo group); 86.1% of the patients had disease that was metastatic at the time of the initial diagnosis. At the data cutoff date for the primary analysis (October 25, 2021), the risk of death was significantly lower, by 32.5%, in the darolutamide group than in the placebo group (hazard ratio 0.68; 95% confidence interval, 0.57 to 0.80; P<0.001). Darolutamide was also associated with consistent benefits with respect to the secondary end points and prespecified subgroups. Adverse events were similar in the two groups, and the incidences of the most common adverse events (occurring in ≥10% of the patients) were highest during the overlapping docetaxel treatment period in both groups. The frequency of grade 3 or 4 adverse events was 66.1% in the darolutamide group and 63.5% in the placebo group; neutropenia was the most common grade 3 or 4 adverse event (in 33.7% and 34.2%, respectively). CONCLUSIONS: In this trial involving patients with metastatic, hormone-sensitive prostate cancer, overall survival was significantly longer with the combination of darolutamide, androgen-deprivation therapy, and docetaxel than with placebo plus androgen-deprivation therapy and docetaxel, and the addition of darolutamide led to improvement in key secondary end points. The frequency of adverse events was similar in the two groups. (Funded by Bayer and Orion Pharma; ARASENS ClinicalTrials.gov number, NCT02799602.).
Assuntos
Antagonistas de Receptores de Andrógenos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Pirazóis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/uso terapêutico , Antagonistas de Receptores de Andrógenos/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Docetaxel/efeitos adversos , Docetaxel/uso terapêutico , Quimioterapia Combinada , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Neutropenia/induzido quimicamente , Modelos de Riscos Proporcionais , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração , Pirazóis/efeitos adversosRESUMO
BACKGROUND: Recently approved treatments and updates to genetic testing recommendations for prostate cancer have created a need for correlated analyses of patient outcomes data via germline genetic mutation status. Genetic registries address these gaps by identifying candidates for recently approved targeted treatments, expanding clinical trial data examining specific gene mutations, and understanding effects of targeted treatments in the real-world setting. METHODS: The PROMISE Registry is a 20-year (5-year recruitment, 15-year follow-up), US-wide, prospective genetic registry for prostate cancer patients. Five thousand patients will be screened through an online at-home germline testing to identify and enroll 500 patients with germline mutations, including: pathogenic or likely pathogenic variants and variants of uncertain significance in genes of interest. Patients will be followed for 15 years and clinical data with real time patient reported outcomes will be collected. Eligible patients will enter long-term follow-up (6-month PRO surveys and medical record retrieval). As a virtual study with patient self-enrollment, the PROMISE Registry may fill gaps in genetics services in underserved areas and for patients within sufficient insurance coverage. RESULTS: The PROMISE Registry opened in May 2021. 2114 patients have enrolled to date across 48 US states and 23 recruiting sites. 202 patients have met criteria for long-term follow-up. PROMISE is on target with the study's goal of 5000 patients screened and 500 patients eligible for long-term follow-up by 2026. CONCLUSIONS: The PROMISE Registry is a novel, prospective, germline registry that will collect long-term patient outcomes data to address current gaps in understanding resulting from recently FDA-approved treatments and updates to genetic testing recommendations for prostate cancer. Through inclusion of a broad nationwide sample, including underserved patients and those unaffiliated with major academic centers, the PROMISE Registry aims to provide access to germline genetic testing and to collect data to understand disease characteristics and treatment responses across the disease spectrum for prostate cancer with rare germline genetic variants.
Assuntos
Mutação em Linhagem Germinativa , Neoplasias da Próstata , Masculino , Humanos , Estudos Prospectivos , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Resultado do Tratamento , Sistema de RegistrosRESUMO
BACKGROUND: In the ARASENS trial (NCT02799602), darolutamide in combination with androgen-deprivation therapy (ADT) and docetaxel significantly reduced the risk of death by 32.5% (HR, 0.68; 95% CI, 0.57-0.80; Pâ <â .0001) compared with placebo plus ADT with docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We present efficacy and safety of darolutamide versus placebo in Black patients from ARASENS. PATIENTS AND METHODS: Patients with mHSPC were randomized 1:1 to darolutamide 600 mg or placebo twice daily in combination with ADT and docetaxel. The primary endpoint was overall survival. Key secondary endpoints included time to castration-resistant prostate cancer (CRPC) and safety. RESULTS: In ARASENS, 54 Black patients received darolutamide (nâ =â 26) or placebo (nâ =â 28) plus ADT and docetaxel. In Black patients, overall survival favored darolutamide versus placebo (median, not reached vs. 38.7 months; stratified HR, 0.41; 95% CI, 0.17-1.02), with 4-year survival rates of 62% versus 41%. The darolutamide group also had longer time to CRPC compared with the placebo group (median, not reached vs .12.6 months; HR, 0.09; 95% CI, 0.02-0.30). The safety profile of darolutamide in Black patients was consistent with that observed for the overall ARASENS population (grade 3/4 treatment-emergent adverse events, TEAEs: 61.5% vs. 66.1%; serious TEAEs: 42.3% vs. 44.8%). CONCLUSION: In this small population of Black patients with mHSPC from the ARASENS trial, darolutamide was associated with an improvement in survival and time to CRPC and was well tolerated. Efficacy and safety findings in Black patients were consistent with the overall ARASENS population.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Pirazóis , Humanos , Masculino , Antagonistas de Androgênios/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Docetaxel/uso terapêutico , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
OPINION STATEMENT: Treatment for metastatic hormone-sensitive prostate cancer has undergone significant evolution in recent years, leading to substantial improvements in overall survival. Men are living longer than ever before with a median survival now which is almost 6 years. The timing and extent of metastatic disease combined with individual patient factors helps treatment recommendation of doublet therapy including androgen deprivation (ADT) plus either chemotherapy or androgen receptor signaling inhibition (ARSI) or triplet therapy with ADT+ARSI+chemotherapy. New treatments must continue to be developed to enhance survival with goals of cure. Better biomarkers that allow for more effective treatments will enhance disease control, quality of life, and survival.
Assuntos
Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/terapia , Antagonistas de Androgênios/uso terapêutico , Qualidade de Vida , Resultado do Tratamento , Hormônios/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
BACKGROUND: Multiple loss-of-function alterations in genes that are involved in DNA repair, including homologous recombination repair, are associated with response to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition in patients with prostate and other cancers. METHODS: We conducted a randomized, open-label, phase 3 trial evaluating the PARP inhibitor olaparib in men with metastatic castration-resistant prostate cancer who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). All the men had a qualifying alteration in prespecified genes with a direct or indirect role in homologous recombination repair. Cohort A (245 patients) had at least one alteration in BRCA1, BRCA2, or ATM; cohort B (142 patients) had alterations in any of 12 other prespecified genes, prospectively and centrally determined from tumor tissue. Patients were randomly assigned (in a 2:1 ratio) to receive olaparib or the physician's choice of enzalutamide or abiraterone (control). The primary end point was imaging-based progression-free survival in cohort A according to blinded independent central review. RESULTS: In cohort A, imaging-based progression-free survival was significantly longer in the olaparib group than in the control group (median, 7.4 months vs. 3.6 months; hazard ratio for progression or death, 0.34; 95% confidence interval, 0.25 to 0.47; P<0.001); a significant benefit was also observed with respect to the confirmed objective response rate and the time to pain progression. The median overall survival in cohort A was 18.5 months in the olaparib group and 15.1 months in the control group; 81% of the patients in the control group who had progression crossed over to receive olaparib. A significant benefit for olaparib was also seen for imaging-based progression-free survival in the overall population (cohorts A and B). Anemia and nausea were the main toxic effects in patients who received olaparib. CONCLUSIONS: In men with metastatic castration-resistant prostate cancer who had disease progression while receiving enzalutamide or abiraterone and who had alterations in genes with a role in homologous recombination repair, olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone. (Funded by AstraZeneca and Merck Sharp & Dohme; PROfound ClinicalTrials.gov number, NCT02987543.).
Assuntos
Antineoplásicos/uso terapêutico , Mutação com Perda de Função , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Androstenos/efeitos adversos , Androstenos/uso terapêutico , Antineoplásicos/efeitos adversos , Proteínas Mutadas de Ataxia Telangiectasia/genética , Benzamidas , Genes BRCA1 , Genes BRCA2 , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Nitrilas , Feniltioidantoína/efeitos adversos , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de Progressão , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologiaRESUMO
BACKGROUND: We previously reported that olaparib led to significantly longer imaging-based progression-free survival than the physician's choice of enzalutamide or abiraterone among men with metastatic castration-resistant prostate cancer who had qualifying alterations in homologous recombination repair genes and whose disease had progressed during previous treatment with a next-generation hormonal agent. The results of the final analysis of overall survival have not yet been reported. METHODS: In an open-label, phase 3 trial, we randomly assigned patients in a 2:1 ratio to receive olaparib (256 patients) or the physician's choice of enzalutamide or abiraterone plus prednisone as the control therapy (131 patients). Cohort A included 245 patients with at least one alteration in BRCA1, BRCA2, or ATM, and cohort B included 142 patients with at least one alteration in any of the other 12 prespecified genes. Crossover to olaparib was allowed after imaging-based disease progression for patients who met certain criteria. Overall survival in cohort A, a key secondary end point, was analyzed with the use of an alpha-controlled, stratified log-rank test at a data maturity of approximately 60%. The primary and other key secondary end points were reported previously. RESULTS: The median duration of overall survival in cohort A was 19.1 months with olaparib and 14.7 months with control therapy (hazard ratio for death, 0.69; 95% confidence interval [CI], 0.50 to 0.97; P = 0.02). In cohort B, the median duration of overall survival was 14.1 months with olaparib and 11.5 months with control therapy. In the overall population (cohorts A and B), the corresponding durations were 17.3 months and 14.0 months. Overall, 86 of 131 patients (66%) in the control group crossed over to receive olaparib (56 of 83 patients [67%] in cohort A). A sensitivity analysis that adjusted for crossover to olaparib showed hazard ratios for death of 0.42 (95% CI, 0.19 to 0.91) in cohort A, 0.83 (95% CI, 0.11 to 5.98) in cohort B, and 0.55 (95% CI, 0.29 to 1.06) in the overall population. CONCLUSIONS: Among men with metastatic castration-resistant prostate cancer who had tumors with at least one alteration in BRCA1, BRCA2, or ATM and whose disease had progressed during previous treatment with a next-generation hormonal agent, those who were initially assigned to receive olaparib had a significantly longer duration of overall survival than those who were assigned to receive enzalutamide or abiraterone plus prednisone as the control therapy, despite substantial crossover from control therapy to olaparib. (Funded by AstraZeneca and Merck Sharp and Dohme; PROfound ClinicalTrials.gov number, NCT02987543.).
Assuntos
Antineoplásicos/uso terapêutico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Proteínas Mutadas de Ataxia Telangiectasia/genética , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Quinases Ciclina-Dependentes/genética , Genes BRCA1 , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica/tratamento farmacológico , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Análise de Sobrevida , Taxoides/uso terapêuticoRESUMO
BACKGROUND: Preliminary trial results showed that enzalutamide significantly improved metastasis-free survival among men who had nonmetastatic, castration-resistant prostate cancer and rapidly increasing prostate-specific antigen (PSA) levels while taking androgen-deprivation therapy. Results from the final analysis of overall survival have not yet been reported. METHODS: In this double-blind, phase 3 trial, men with nonmetastatic, castration-resistant prostate cancer (defined on the basis of conventional imaging and a PSA doubling time of ≤10 months) who were continuing to receive androgen-deprivation therapy were randomly assigned (in a 2:1 ratio) to receive enzalutamide at a dose of 160 mg or placebo once daily. Overall survival was assessed with a group sequential testing procedure and an O'Brien-Fleming-type alpha-spending function. RESULTS: As of October 15, 2019, a total of 288 of 933 patients (31%) in the enzalutamide group and 178 of 468 (38%) in the placebo group had died. Median overall survival was 67.0 months (95% confidence interval [CI], 64.0 to not reached) in the enzalutamide group and 56.3 months (95% CI, 54.4 to 63.0) in the placebo group (hazard ratio for death, 0.73; 95% CI, 0.61 to 0.89; P = 0.001). The exposure-adjusted rate of adverse events of grade 3 or higher was 17 per 100 patient-years in the enzalutamide group and 20 per 100 patient-years in the placebo group. Adverse events in the enzalutamide group were consistent with those previously reported for enzalutamide; the most frequently reported events were fatigue and musculoskeletal events. CONCLUSIONS: Enzalutamide plus androgen-deprivation therapy resulted in longer median overall survival than placebo plus androgen-deprivation therapy among men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA level. The risk of death associated with enzalutamide was 27% lower than with placebo. Adverse events were consistent with the established safety profile of enzalutamide. (Funded by Pfizer and Astellas Pharma; PROSPER ClinicalTrials.gov number, NCT02003924.).
Assuntos
Adenocarcinoma/tratamento farmacológico , Antagonistas de Androgênios/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Adenocarcinoma/mortalidade , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas , Método Duplo-Cego , Humanos , Calicreínas/sangue , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Nitrilas , Feniltioidantoína/efeitos adversos , Feniltioidantoína/uso terapêutico , Placebos , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/mortalidade , Análise de SobrevidaRESUMO
PURPOSE: This post hoc analysis of PROSPER evaluated the relationship between depth of PSA decline and clinical outcomes in enzalutamide-treated men with nonmetastatic castration-resistant prostate cancer. MATERIALS AND METHODS: PROSPER was an international, randomized, double-blind, placebo-controlled, phase 3 trial that demonstrated significantly improved metastasis-free survival and overall survival with androgen deprivation therapy plus enzalutamide vs placebo. A total of 905 enzalutamide-treated men were included in this post hoc analysis. Metastasis-free survival (primary endpoint) and overall survival (secondary endpoint) were evaluated for 4 mutually exclusive subgroups defined by PSA decline: <50% (reference); ≥50% to <90%; ≥90%, nadir ≥0.2 ng/mL; and ≥90%, nadir <0.2 ng/mL. Medians and 95% confidence intervals were determined using a 12-month landmark analysis; hazard ratios and P values were based on an unstratified Cox proportional analysis model. RESULTS: In enzalutamide-treated men, PSA declines of <50%, ≥50% to <90%, ≥90% with nadir ≥0.2 ng/mL, and ≥90% with nadir <0.2 ng/mL were associated with median metastasis-free survival in months (95% confidence intervals) of 22.1 (14.8-not reached), 34.2 (29.4-not reached), 36.6 (33.4-not reached), and not reached, respectively, and overall survival in months (95% confidence intervals) of 40.8 (31.7-44.9), 54.4 (49.0-67.0), 64.3 (63.4-not reached), and not reached, respectively. CONCLUSIONS: There was a statistically significant correlation between greater depth of PSA decline and improved clinical outcomes, suggesting a previously underappreciated relationship between changes in PSA levels and clinical outcomes in nonmetastatic castration-resistant prostate cancer.
Assuntos
Antineoplásicos , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Antagonistas de Androgênios/uso terapêutico , Antineoplásicos/uso terapêutico , Nitrilas/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/patologia , Resultado do TratamentoRESUMO
BACKGROUND: Studies have shown that infant temperament varies with maternal psychosocial factors, in utero illness, and environmental stressors. We predicted that the pandemic would shape infant temperament through maternal SARS-CoV-2 infection during pregnancy and/or maternal postnatal stress. To test this, we examined associations among infant temperament, maternal prenatal SARS-CoV-2 infection, maternal postnatal stress, and postnatal COVID-related life disruptions. METHODS: We tested 63 mother-infant dyads with prenatal maternal SARS-CoV-2 infections and a comparable group of 110 dyads without infections. To assess postnatal maternal stress, mothers completed the Perceived Stress Scale 4 months postpartum and an evaluation of COVID-related stress and life disruptions 6 months postpartum. Mothers reported on infant temperament when infants were 6-months-old using the Infant Behavior Questionnaire-Revised (IBQ-R) Very Short Form. RESULTS: Maternal SARS-CoV-2 infection during pregnancy was not associated with infant temperament or maternal postnatal stress. Mothers with higher self-reported postnatal stress rated their infants lower on the Positive Affectivity/Surgency and Orienting/Regulation IBQ-R subscales. Mothers who reported greater COVID-related life disruptions rated their infants higher on the Negative Emotionality IBQ-R subscale. CONCLUSIONS: Despite no effect of prenatal maternal SARS-CoV-2 infection, stress and life disruptions incurred by the COVID-19 pandemic were associated with infant temperament at 6-months. IMPACT: SARS-CoV-2 infection during pregnancy is not associated with postnatal ratings of COVID-related life disruptions, maternal stress, or infant temperament. Postnatal ratings of maternal stress during the COVID-19 pandemic are associated with normative variation in maternal report of infant temperament at 6 months of age. Higher postnatal ratings of maternal stress are associated with lower scores on infant Positive Affectivity/Surgency and Orienting/Regulation at 6 months of age. Higher postnatal ratings of COVID-related life disruptions are associated with higher scores on infant Negative Emotionality at 6 months of age.
Assuntos
COVID-19 , Temperamento , Feminino , Humanos , Lactente , Temperamento/fisiologia , Pandemias , SARS-CoV-2 , Mães/psicologia , Comportamento do Lactente/fisiologia , Comportamento do Lactente/psicologiaRESUMO
WHAT IS THIS SUMMARY ABOUT?: This is a summary of a research article originally published in the Journal of Urology. The PROSPER study involved men who had a type of advanced prostate cancer called non-metastatic castration-resistant prostate cancer (nmCRPC). In patients with nmCRPC, their prostate cancer keeps growing even after traditional hormone treatments. In these patients, rising prostate-specific antigen (PSA) levels suggest that cancer is active but CT and bone scans show that it has not spread to other parts of the body. Everyone in this study received androgen deprivation therapy (ADT) either with the medicine enzalutamide or a placebo. Enzalutamide is a medicine that can slow or stop androgens, such as testosterone, from making prostate cancer grow. The main results of the PROSPER study showed that patients with nmCRPC treated with enzalutamide and ADT lived longer than patients treated with placebo and ADT. In this study, researchers wanted to know if the findings were different depending on how much patients' PSA level declined after enzalutamide treatment. Researchers also wanted to know if this made a difference in how long patients lived without the cancer spreading to other parts of their body. WHAT WERE THE RESULTS?: Researchers found that patients with a large decline in PSA level after treatment were more likely to live longer and without their cancer spreading. WHAT DO THE RESULTS MEAN?: This study shows a link between PSA level changes and how long patients with nmCRPC live when treated with enzalutamide and ADT. These results may help health professionals monitor patients with different PSA level changes after enzalutamide treatment. Patients with a large decline in PSA level may not need to be monitored as closely as patients with a small decline in PSA level.
RESUMO
BACKGROUND: The PROfound study showed significantly improved radiographical progression-free survival and overall survival in men with metastatic castration-resistant prostate cancer with alterations in homologous recombination repair genes and disease progression on a previous next-generation hormonal drug who received olaparib then those who received control. We aimed to assess pain and patient-centric health-related quality of life (HRQOL) measures in patients in the trial. METHODS: In this open-label, randomised, phase 3 study, patients (aged ≥18 years) with metastatic castration-resistant prostate cancer and gene alterations to one of 15 genes (BRCA1, BRCA2, or ATM [cohort A] and BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L [cohort B]) and disease progression after a previous next-generation hormonal drug were randomly assigned (2:1) to receive olaparib tablets (300 mg orally twice daily) or a control drug (enzalutamide tablets [160 mg orally once daily] or abiraterone tablets [1000 mg orally once daily] plus prednisone tablets [5 mg orally twice daily]), stratified by previous taxane use and measurable disease. The primary endpoint (radiographical progression-free survival in cohort A) has been previously reported. The prespecified secondary endpoints reported here are on pain, HRQOL, symptomatic skeletal-related events, and time to first opiate use for cancer-related pain in cohort A. Pain was assessed with the Brief Pain Inventory-Short Form, and HRQOL was assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P). All endpoints were analysed in patients in cohort A by modified intention-to-treat. The study is registered with ClinicalTrials.gov, NCT02987543. FINDINGS: Between Feb 6, 2017, and June 4, 2019, 245 patients were enrolled in cohort A and received study treatment (162 [66%] in the olaparib group and 83 [34%] in the control group). Median duration of follow-up at data cutoff in all patients was 6·2 months (IQR 2·2-10·4) for the olaparib group and 3·5 months (1·7-4·9) for the control group. In cohort A, median time to pain progression was significantly longer with olaparib than with control (median not reached [95% CI not reached-not reached] with olaparib vs 9·92 months [5·39-not reached] with control; HR 0·44 [95% CI 0·22-0·91]; p=0·019). Pain interference scores were also better in the olaparib group (difference in overall adjusted mean change from baseline score -0·85 [95% CI -1·31 to -0·39]; pnominal=0·0004). Median time to progression of pain severity was not reached in either group (95% CI not reached-not reached for both groups; HR 0·56 [95% CI 0·25-1·34]; pnominal=0·17). In patients who had not used opiates at baseline (113 in the olaparib group, 58 in the control group), median time to first opiate use for cancer-related pain was 18·0 months (95% CI 12·8-not reached) in the olaparib group versus 7·5 months (3·2-not reached) in the control group (HR 0·61; 95% CI 0·38-0·99; pnominal=0·044). The proportion of patients with clinically meaningful improvement in FACT-P total score during treatment was higher for the olaparib group than the control group: 15 (10%) of 152 evaluable patients had a response in the olaparib group compared with one (1%) of evaluable 77 patients in the control group (odds ratio 8·32 [95% CI 1·64-151·84]; pnominal=0·0065). Median time to first symptomatic skeletal-related event was not reached for either treatment group (olaparib group 95% CI not reached-not reached; control group 7·8-not reached; HR 0·37 [95% CI 0·20-0·70]; pnominal=0·0013). INTERPRETATION: Olaparib was associated with reduced pain burden and better-preserved HRQOL compared with the two control drugs in men with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations who had disease progression after a previous next-generation hormonal drug. Our findings support the clinical benefit of improved radiographical progression-free survival and overall survival identified in PROfound. FUNDING: AstraZeneca and Merck Sharp & Dohme.
Assuntos
Médicos , Neoplasias de Próstata Resistentes à Castração , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Humanos , Masculino , Dor/tratamento farmacológico , Ftalazinas , Piperazinas , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Qualidade de Vida , Reparo de DNA por RecombinaçãoRESUMO
BACKGROUND: E3805 (CHAARTED) is a phase 3 trial demonstrating improved survival for men with metastatic hormone-sensitive prostate cancer (mHSPC) randomized to treatment with docetaxel (D) and androgen-deprivation therapy (ADT) versus ADT alone. We assessed the association of baseline body mass index (BMI) and metformin exposure with quality of life (QOL) and prostate cancer outcomes including survival in patients enrolled in the CHAARTED study. METHODS: We performed a posthoc exploratory analysis of the CHAARTED trial of men with mHSPC randomized to treatment with ADT with or without D between 2006 and 2012. Cox proportional hazards models and Kruskal-Wallis test were used to evaluate the association between BMI with QOL and prostate cancer outcomes and between metformin exposure and survival. RESULTS: In 788 of 790 enrolled patients with prospectively recorded baseline BMI and metformin exposure status, lower BMI was not associated with survival, but was associated with high volume disease (p < 0.0001) and poorer baseline QOL on functional assessment of cancer therapy-prostate (p = 0.008). Only 68 patients had prevalent metformin exposure at baseline in the CHAARTED trial. Four groups were identified: ADT + D + metformin (n = 39); ADT + D (n = 357); ADT + metformin (n = 29); and ADT alone (n = 363). Baseline clinicopathologic characteristics were similar between groups. In this small exploratory multivariable analysis, metformin exposure was not associated with survival (hazard ratio: 1.15; 95% confidence interval: 0.81-1.63, p = 0.44). CONCLUSIONS: There was no link between baseline BMI and survival, but lower baseline BMI was associated with features of greater cancer burden and poorer QOL.
Assuntos
Metformina , Neoplasias da Próstata , Antagonistas de Androgênios/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Índice de Massa Corporal , Hormônios/uso terapêutico , Humanos , Masculino , Metformina/uso terapêutico , Neoplasias da Próstata/patologia , Qualidade de VidaRESUMO
WHAT IS THIS SUMMARY ABOUT?: This is a summary of a publication about the ARASENS trial, which was published in the New England Journal of Medicine in February 2022. The trial includes 1,306 men with a type of prostate cancer called metastatic, hormone-sensitive prostate cancer (also called mHSPC). In the trial, researchers wanted to learn if combining a treatment called darolutamide (also known by the brand name Nubeqa®) with two other medicines called androgen deprivation therapy (also called ADT) and docetaxel (brand name Taxotere®) could help treat patients with mHSPC better than placebo plus ADT and docetaxel. ADT with docetaxel is a treatment used for patients with mHSPC. Darolutamide is an approved treatment for a different type of prostate cancer called non-metastatic, castration-resistant prostate cancer (also called nmCRPC). WHAT WERE THE RESULTS?: The trial results showed that combining darolutamide with ADT and docetaxel increased the chance of survival and lowered the risk of death by 32.5% compared to combining ADT and docetaxel with placebo instead. Compared to patients who received the placebo, patients who received darolutamide had a delay in: their cancer becoming castration-resistant worsening pain having cancer-related bone fractures or related symptoms needing additional therapies for cancer The percentage of trial patients who had medical problems during the trial, also called adverse events, was similar between trial patients who received darolutamide and those who received the placebo. WHAT DO THE RESULTS OF THE STUDY MEAN?: Combining darolutamide with ADT and docetaxel helped treat trial patients with mHSPC better than placebo with ADT and docetaxel. Darolutamide in combination with ADT and docetaxel could be a treatment option for patients with mHSPC. Patients should always talk to their doctors and nurses before making any decisions about their treatment. This summary also includes perspectives on the ARASENS trial and prostate cancer from 3 members of the patient community. ClinicalTrials.gov NCT number: NCT02799602.
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Antagonistas de Androgênios , Neoplasias da Próstata , Antagonistas de Androgênios/administração & dosagem , Antagonistas de Androgênios/efeitos adversos , Cuidadores , Docetaxel/uso terapêutico , Hormônios , Humanos , Idioma , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , PirazóisRESUMO
WHAT IS THIS SUMMARY ABOUT?: This is a summary of a research article originally published in European Journal of Cancer. The PROSPER study involved men who had a type of advanced prostate cancer called nonmetastatic castration-resistant prostate cancer (nmCRPC). In men with nmCRPC, their cancer has progressed on traditional hormone therapy but scans show that it has not spread to other parts of the body. The main results of the PROSPER study showed that patients treated with enzalutamide lived longer than patients treated with placebo. For this analysis, researchers looked at whether this was different depending on patients' traits. WHAT WERE THE RESULTS?: Researchers found that age and location did not affect how long patients lived when treated with enzalutamide. They found three patient traits that did make a difference. Being able to carry out daily activities, low prostate-specific antigen level (PSA level), and receiving no other prostate cancer treatments after the study meant that patients were more likely to live longer. WHAT DO THE RESULTS OF THE STUDY MEAN?: Patients with nmCRPC treated with enzalutamide lived longer than patients treated with placebo. Age and location did not affect how long these patients lived, but other traits did. Clinical Trial Registration: NCT02003924 (ClinicalTrials.gov).
Assuntos
Antagonistas de Androgênios , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Antagonistas de Androgênios/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/patologia , Androgênios , Feniltioidantoína/administração & dosagem , Nitrilas/uso terapêuticoRESUMO
BACKGROUND: The Phase III PROfound study (NCT02987543) evaluated olaparib versus abiraterone or enzalutamide (control; randomized 2:1 to olaparib or control) in men with homologous recombination repair gene alterations and metastatic castration-resistant prostate cancer whose disease progressed on prior next-generation hormonal agent. METHODS: We present efficacy and safety data from an exploratory post hoc analysis of olaparib in the PROfound Asian subset. Analyses were not planned, alpha controlled or powered. Of 101 Asian patients enrolled in Japan (n=57), South Korea (n=29) and Taiwan (n=15), 66 and 35 patients received olaparib and control, respectively. RESULTS: Radiographic progression-free survival (rPFS) and overall survival (OS) favored olaparib versus control in Cohort A [rPFS 7.2 vs. 4.5 months, HR 0.58, 95% CI 0.29-1.21, P = 0.14 (nominal); OS 23.4 vs. 17.8 months, HR 0.81, 95% CI 0.40-1.74, P = 0.57 (nominal)] and Cohorts A+B [rPFS 5.8 vs. 3.5 months, HR 0.69, 95% CI 0.42-1.16, P = 0.13 (nominal); OS 18.6 vs. 16.2 months, HR 0.96, 95% CI 0.56-1.70, P = 0.9 (nominal)]. Olaparib showed greatest improvement in patients harboring BRCA alterations [rPFS 9.3 vs. 3.5 months, HR 0.17, 95% CI 0.06-0.49, P = 0.0003 (nominal); OS 26.8 vs. 14.3 months, HR 0.62, 95% CI 0.24-1.79, P = 0.34 (nominal)]. Safety data were consistent with the known profile of olaparib, with no new safety signals identified. CONCLUSION: In PROfound, there was a statistically significant improvement in outcomes reported in the global population of patients with metastatic castration-resistant prostate cancer and alterations in homologous recombination repair genes whose disease progressed on prior next-generation hormonal agent compared with control. For the subset of Asian patients reported here, exploratory analysis suggested that there was also an improvement in outcomes versus control. The safety and tolerability of olaparib in Asian patients were similar to that of the PROfound global population. CLINICAL TRIAL NUMBER: ClinicalTrials.gov NCT02987543.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Protocolos de Quimioterapia Combinada Antineoplásica , Humanos , Masculino , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Reparo de DNA por RecombinaçãoRESUMO
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 200 million people worldwide and has likely exposed millions of neonates to SARS-CoV-2 in utero. A large body of literature has examined the possibility of vertical transmission from pregnant women infected with SARS-CoV-2 to their neonates. In this chapter, we review mechanisms of-and evidence for-vertical transmission of SARS-CoV-2, including transplacental, through other biospecimens and breastfeeding, and discuss neonatal outcomes following in utero exposure. Based on the available literature, we conclude vertical transmission of SARS-CoV-2 is rare, and exposed neonates generally show favorable health outcomes.
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COVID-19 , Feminino , Humanos , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas , Gravidez , SARS-CoV-2RESUMO
BACKGROUND: Despite standard curative-intent treatment with neoadjuvant cisplatin-based chemotherapy, followed by radical surgery in eligible patients, muscle-invasive urothelial carcinoma has a high recurrence rate and no level 1 evidence for adjuvant therapy. We aimed to evaluate atezolizumab as adjuvant therapy in patients with high-risk muscle-invasive urothelial carcinoma. METHOD: In the IMvigor010 study, a multicentre, open-label, randomised, phase 3 trial done in 192 hospitals, academic centres, and community oncology practices across 24 countries or regions, patients aged 18 years and older with histologically confirmed muscle-invasive urothelial carcinoma and an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 were enrolled within 14 weeks after radical cystectomy or nephroureterectomy with lymph node dissection. Patients had ypT2-4a or ypN+ tumours following neoadjuvant chemotherapy or pT3-4a or pN+ tumours if no neoadjuvant chemotherapy was received. Patients not treated with neoadjuvant chemotherapy must have been ineligible for or declined cisplatin-based adjuvant chemotherapy. No post-surgical radiotherapy or previous adjuvant chemotherapy was allowed. Patients were randomly assigned (1:1) using a permuted block (block size of four) method and interactive voice-web response system to receive 1200 mg atezolizumab given intravenously every 3 weeks for 16 cycles or up to 1 year, whichever occurred first, or to observation. Randomisation was stratified by previous neoadjuvant chemotherapy use, number of lymph nodes resected, pathological nodal status, tumour stage, and PD-L1 expression on tumour-infiltrating immune cells. The primary endpoint was disease-free survival in the intention-to-treat population. Safety was assessed in patients who either received at least one dose of atezolizumab or had at least one post-baseline safety assessment. This trial is registered with ClinicalTrials.gov, NCT02450331, and is ongoing but not recruiting patients. FINDINGS: Between Oct 5, 2015, and July 30, 2018, we enrolled 809 patients, of whom 406 were assigned to the atezolizumab group and 403 were assigned to the observation group. Median follow-up was 21·9 months (IQR 13·2-29·8). Median disease-free survival was 19·4 months (95% CI 15·9-24·8) with atezolizumab and 16·6 months (11·2-24·8) with observation (stratified hazard ratio 0·89 [95% CI 0·74-1·08]; p=0·24). The most common grade 3 or 4 adverse events were urinary tract infection (31 [8%] of 390 patients in the atezolizumab group vs 20 [5%] of 397 patients in the observation group), pyelonephritis (12 [3%]) vs 14 [4%]), and anaemia (eight [2%] vs seven [2%]). Serious adverse events occurred in 122 (31%) patients who received atezolizumab and 71 (18%) who underwent observation. 63 (16%) patients who received atezolizumab had a treatment-related grade 3 or 4 adverse event. One treatment-related death, due to acute respiratory distress syndrome, occurred in the atezolizumab group. INTERPRETATION: To our knowledge, IMvigor010 is the largest, first-completed phase 3 adjuvant study to evaluate the role of a checkpoint inhibitor in muscle-invasive urothelial carcinoma. The trial did not meet its primary endpoint of improved disease-free survival in the atezolizumab group over observation. Atezolizumab was generally tolerable, with no new safety signals; however, higher frequencies of adverse events leading to discontinuation were reported than in metastatic urothelial carcinoma studies. These data do not support the use of adjuvant checkpoint inhibitor therapy in the setting evaluated in IMvigor010 at this time. FUNDING: F Hoffmann-La Roche/Genentech.