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BACKGROUND: Co-inhibition of poly(ADP-ribose) polymerase (PARP) and androgen receptor activity might result in antitumour efficacy irrespective of alterations in DNA damage repair genes involved in homologous recombination repair (HRR). We aimed to compare the efficacy and safety of talazoparib (a PARP inhibitor) plus enzalutamide (an androgen receptor blocker) versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: TALAPRO-2 is a randomised, double-blind, phase 3 trial of talazoparib plus enzalutamide versus placebo plus enzalutamide as first-line therapy in men (age ≥18 years [≥20 years in Japan]) with asymptomatic or mildly symptomatic mCRPC receiving ongoing androgen deprivation therapy. Patients were enrolled from 223 hospitals, cancer centres, and medical centres in 26 countries in North America, Europe, Israel, South America, South Africa, and the Asia-Pacific region. Patients were prospectively assessed for HRR gene alterations in tumour tissue and randomly assigned (1:1) to talazoparib 0·5 mg or placebo, plus enzalutamide 160 mg, administered orally once daily. Randomisation was stratified by HRR gene alteration status (deficient vs non-deficient or unknown) and previous treatment with life-prolonging therapy (docetaxel or abiraterone, or both: yes vs no) in the castration-sensitive setting. The sponsor, patients, and investigators were masked to talazoparib or placebo, while enzalutamide was open-label. The primary endpoint was radiographic progression-free survival (rPFS) by blinded independent central review, evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT03395197) and is ongoing. FINDINGS: Between Jan 7, 2019, and Sept 17, 2020, 805 patients were enrolled and randomly assigned (402 to the talazoparib group and 403 to the placebo group). Median follow-up for rPFS was 24·9 months (IQR 21·9-30·2) for the talazoparib group and 24·6 months (14·4-30·2) for the placebo group. At the planned primary analysis, median rPFS was not reached (95% CI 27·5 months-not reached) for talazoparib plus enzalutamide and 21·9 months (16·6-25·1) for placebo plus enzalutamide (hazard ratio 0·63; 95% CI 0·51-0·78; p<0·0001). In the talazoparib group, the most common treatment-emergent adverse events were anaemia, neutropenia, and fatigue; the most common grade 3-4 event was anaemia (185 [46%] of 398 patients), which improved after dose reduction, and only 33 (8%) of 398 patients discontinued talazoparib due to anaemia. Treatment-related deaths occurred in no patients in the talazoparib group and two patients (<1%) in the placebo group. INTERPRETATION: Talazoparib plus enzalutamide resulted in clinically meaningful and statistically significant improvement in rPFS versus standard of care enzalutamide as first-line treatment for patients with mCRPC. Final overall survival data and additional long-term safety follow-up will further clarify the clinical benefit of the treatment combination in patients with and without tumour HRR gene alterations. FUNDING: Pfizer.
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Anemia , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Adolescente , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos , Antagonistas de Androgênios/uso terapêutico , Anemia/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , Método Duplo-CegoRESUMO
BACKGROUND: There is an ongoing debate as to whether sex could be associated with immune checkpoint inhibitor (ICI) benefit. Existing literature data reveal contradictory results, and data on first-line immune combinations are lacking. METHOD: This was a real-world, multicenter, international, observational study to determine the sex effects on the clinical outcomes in metastatic renal cell carcinoma (mRCC) patients treated with immuno-oncology combinations as first-line therapy. RESULTS: A total of 1827 mRCC patients from 71 cancer centers in 21 countries were included. The median OS was 38.7 months (95% CI 32.7-44.2) in the overall study population: 40.0 months (95% CI 32.7-51.6) in males and 38.7 months (95% CI 26.4-41.0) in females (p = 0.202). The median OS was higher in males vs. females in patients aged 18-49y (36.9 months, 95% CI 29.0-51.6, vs. 24.8 months, 95% CI 16.8-40.4, p = 0.426, with + 19% of 2y-OS rate, 72% vs. 53%, p = 0.006), in the clear cell histology subgroup (44.2 months, 95% CI 35.8-55.7, vs. 38.7 months, 95% CI 26.0-41.0, p = 0.047), and in patients with sarcomatoid differentiation (34.4 months, 95% CI 26.4-59.0, vs. 15.3 months, 95% CI 8.9-41.0, p < 0.001). Sex female was an independent negative prognostic factor in the sarcomatoid population (HR 1.72, 95% CI 1.15 - 2.57, p = 0.008). CONCLUSIONS: Although the female's innate and adaptive immunity has been observed to be more active than the male's, women in the subgroup of clear cell histology, sarcomatoid differentiation, and those under 50 years of age showed shorter OS than males.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Feminino , Masculino , Pessoa de Meia-Idade , Neoplasias Renais/mortalidade , Neoplasias Renais/imunologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Adulto , Idoso , Adulto Jovem , Adolescente , Fatores Sexuais , Inibidores de Checkpoint Imunológico/uso terapêutico , Prognóstico , Imunoterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Taxa de Sobrevida , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Immune checkpoint inhibitors have changed previous treatment paradigm of advanced urothelial carcinoma (UC). The ARON-2 study (NCT05290038) aimed to assess the real-world effectiveness of pembrolizumab in patients recurred or progressed after platinum-based chemotherapy. PATIENTS AND METHODS: Medical records of patients with documented metastatic UC treated by pembrolizumab as second-line therapy were retrospectively collected from 88 institutions in 23 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Cox proportional hazards models were adopted to explore the presence of prognostic factors. RESULTS: In total, 836 patients were included: 544 patients (65%) received pembrolizumab after progression to first-line platinum-based chemotherapy in the metastatic setting (cohort A) and 292 (35%) after recurring within < 12 months since the completion of adjuvant or neoadjuvant chemotherapy (cohort B). The median follow-up time was 15.3 months. The median OS and the ORR were 10.5 months and 31% in the overall study population, 9.1 months and 29% in cohort A and 14.6 months and 37% in cohort B. At multivariate analysis, ECOG-PS ≥ 2, bone metastases, liver metastases and pembrolizumab setting (cohort A vs B) proved to be significantly associated with worst OS and PFS. Stratified by the presence of 0, 1-2 or 3-4 prognostic factors, the median OS was 29.4, 12.5 and 4.1 months (p < 0.001), while the median PFS was 12.2, 6.4 and 2.8 months, respectively (p < 0.001). CONCLUSIONS: Our study confirms that pembrolizumab is effective in the advanced UC real-world context, showing outcome differences between patients recurred or progressed after platinum-based chemotherapy.
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Anticorpos Monoclonais Humanizados , Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Adjuvantes Imunológicos , Platina , Estudos RetrospectivosRESUMO
WHAT IS THIS SUMMARY ABOUT?: This summary describes the results from the TALAPRO-2 research study (also known as a clinical trial). The TALAPRO-2 study tested the combination of two medicines called talazoparib plus enzalutamide. This combination of medicines was used as the first treatment for adult patients with metastatic castration-resistant prostate cancer. The combination of talazoparib plus enzalutamide was compared with a placebo plus enzalutamide. WHAT IS METASTATIC CASTRATION-RESISTANT PROSTATE CANCER?: Metastatic castration-resistant prostate cancer is a type of cancer that starts in the prostate and has spread to other parts of the body. Castration-resistant means that the cancer continues to grow even when testosterone levels in the blood are reduced to very low levels. Taking medicines to lower testosterone levels in the blood is a standard treatment for men with advanced prostate cancer. WHAT ARE THE AIMS OF THE TALAPRO-2 TRIAL?: TALAPRO-2 looked at if combining talazoparib plus enzalutamide would increase the length of time patients lived before their cancer got worse or they died compared with a placebo plus enzalutamide. Researchers looked at how treatment affected the size and number of tumors and the length of time before patients needed to change to a new cancer medicine. Researchers also looked at any side effects patients had during the study. WHAT ARE THE KEY TAKEAWAYS?: A total of 805 patients with metastatic castration-resistant prostate cancer took part in the study. Compared with patients who took a placebo plus enzalutamide, the group of patients who took talazoparib plus enzalutamide had a 37% reduced risk of their cancer getting worse or dying. Some patients had tumors that at the start of the study could be measured with scans. Sixty-two percent of patients who took talazoparib plus enzalutamide had their tumors decrease or shrink to the point that they could no longer be seen on scans versus 44% of patients who took a placebo plus enzalutamide. Patients who took talazoparib plus enzalutamide were more likely to have a longer time before they needed to change to a new cancer medicine. The most common side effects of talazoparib plus enzalutamide were low levels of red blood cells (66% of patients) and neutrophils (36% of patients), and excessive tiredness or exhaustion (34% of patients).Clinical Trial Registration: NCT03395197 (TALAPRO-2) (ClinicalTrials.gov).
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BACKGROUND: Concomitant medications may potentially affect the outcome of cancer patients. In this sub-analysis of the ARON-2 real-world study (NCT05290038), we aimed to assess the impact of concomitant use of proton pump inhibitors (PPI), statins, or metformin on outcome of patients with metastatic urothelial cancer (mUC) receiving second-line pembrolizumab. METHODS: We collected data from the hospital medical records of patients with mUC treated with pembrolizumab as second-line therapy at 87 institutions from 22 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate. We carried out a survival analysis by a Cox regression model. RESULTS: A total of 802 patients were eligible for this retrospective study; the median follow-up time was 15.3 months. PPI users compared to non-users showed inferior PFS (4.5 vs. 7.2 months, p = 0.002) and OS (8.7 vs. 14.1 months, p < 0.001). Concomitant PPI use remained a significant predictor of PFS and OS after multivariate Cox analysis. The use of statins or metformin was not associated with response or survival. CONCLUSIONS: Our study results suggest a significant prognostic impact of concomitant PPI use in mUC patients receiving pembrolizumab in the real-world context. The mechanism of this interaction warrants further elucidation.
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Carcinoma de Células de Transição , Inibidores de Hidroximetilglutaril-CoA Redutases , Metformina , Neoplasias da Bexiga Urinária , Humanos , Inibidores da Bomba de Prótons , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Metformina/uso terapêutico , Estudos RetrospectivosRESUMO
Grignard Pure (GP) is a unique and proprietary blend of triethylene glycol (TEG) and inert ingredients designed for continuous antimicrobial treatment of air. TEG has been designated as a â³Safer Chemical" by the US EPA. GP has already received approval from the US EPA under its Section 18 Public Health Emergency Exemption program for use in seven states. This study characterizes the efficacy of GP for inactivating MS2 bacteriophageâa nonenveloped virus widely used as a surrogate for SARS-CoV-2. Experiments measured the decrease in airborne viable MS2 concentration in the presence of different concentrations of GP from 60 to 90 min, accounting for both natural die-off and settling of MS2. Experiments were conducted both by introducing GP aerosol into air containing MS2 and by introducing airborne MS2 into air containing GP aerosol. GP is consistently able to rapidly reduce viable MS2 bacteriophage concentration by 2-3â¯logs at GP concentrations of 0.04-0.5 mg/m3 (corresponding to TEG concentrations of 0.025 to 0.287 mg/m3). Related GP efficacy experiments by the US EPA, as well as GP (TEG) safety and toxicology, are also discussed.
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Anti-Infecciosos , COVID-19 , Humanos , SARS-CoV-2 , Levivirus , Aerossóis e Gotículas RespiratóriosRESUMO
WHAT IS THIS SUMMARY ABOUT?: This summary describes the design of an ongoing research study (also known as a clinical trial) called TALAPRO-2. The TALAPRO-2 trial is testing the combination of two medicines called talazoparib and enzalutamide as a first treatment in adult men with metastatic castration-resistant prostate cancer. The study began in December 2017 and has enrolled 1037 adult men with metastatic castration-resistant prostate cancer from 26 countries. WHAT IS METASTATIC CASTRATION-RESISTANT PROSTATE CANCER?: Metastatic castration-resistant prostate cancer is a type of cancer that has advanced beyond the prostate and continues to grow even when testosterone levels in the blood are suppressed. WHICH MEDICINES ARE BEING TESTED?: The combination of talazoparib plus enzalutamide will be compared with enzalutamide plus placebo. Enzalutamide is approved to treat men with prostate cancer. Talazoparib is not approved to treat men with prostate cancer. A placebo does not contain any active ingredients and is also known as a sugar pill. WHAT ARE THE AIMS OF THE TALAPRO-2 TRIAL?: The TALAPRO-2 trial will find out if combining talazoparib with enzalutamide increases the length of time the men in the study live without their cancer getting worse compared with enzalutamide plus placebo. The study will also measure how long men in the study live and any side effects the men have while they are taking the study medicines. Researchers are also testing the DNA from the tumor cells of all men in the study to find out if they have faulty DNA repair genes. Clinical Trial Registration: NCT0339519 (ClinicalTrials.gov).
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Antineoplásicos , Neoplasias de Próstata Resistentes à Castração , Adulto , Antineoplásicos/uso terapêutico , Benzamidas , Ensaios Clínicos como Assunto , Humanos , Idioma , Masculino , Nitrilas/uso terapêutico , Feniltioidantoína , Ftalazinas , Neoplasias de Próstata Resistentes à Castração/patologia , Açúcares/uso terapêutico , TestosteronaRESUMO
PARP inhibitors in combination with androgen receptor-targeted therapy have demonstrated potential in the treatment of metastatic castration-resistant prostate cancer (mCRPC). Here, we describe the design and rationale of the multinational, phase III, two-part TALAPRO-2 study comparing talazoparib plus enzalutamide versus placebo plus enzalutamide as a first-line treatment for patients with mCRPC with or without DNA damage response (DDR) alterations. This study has two co-primary end points: radiographic progression-free survival (rPFS) by blinded independent clinical review in all-comers (cohort 1) and in patients with DDR alterations (cohort 2). TALAPRO-2 will demonstrate whether talazoparib plus enzalutamide can significantly improve the efficacy of enzalutamide in terms of rPFS in both molecularly unselected and DDR-deficient patients with mCRPC (NCT03395197). Clinical Trial Registration: NCT03395197 (ClinicalTrials.gov).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/uso terapêutico , Nitrilas/uso terapêutico , Feniltioidantoína/uso terapêutico , Ftalazinas/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Antagonistas de Receptores de Andrógenos/uso terapêutico , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/genética , Humanos , Masculino , Metástase Neoplásica , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Intervalo Livre de Progressão , Neoplasias de Próstata Resistentes à Castração/patologiaRESUMO
The mechanistic target of rapamycin (mTOR) is an established therapeutic target in renal cell carcinoma (RCC). Mechanisms of secondary resistance to rapalog therapy in RCC have not been studied previously. We identified six patients with metastatic RCC who initially responded to mTOR inhibitor therapy and then progressed, and had pre-treatment and post-treatment tumor samples available for analysis. We performed deep whole exome sequencing on the paired tumor samples and a blood sample. Sequence data was analyzed using Mutect, CapSeg, Absolute, and Phylogic to identify mutations, copy number changes, and their changes over time. We also performed in vitro functional assays on PBRM1 in RCC cell lines. Five patients had clear cell and one had chromophobe RCC. 434 somatic mutations in 416 genes were identified in the 12 tumor samples. 201 (46%) of mutations were clonal in both samples while 129 (30%) were acquired in the post-treatment samples. Tumor heterogeneity or sampling issues are likely to account for some mutations that were acquired in the post-treatment samples. Three samples had mutations in TSC1; one in PTEN; and none in MTOR. PBRM1 was the only gene in which mutations were acquired in more than one post-treatment sample. We examined the effect of PBRM1 loss in multiple RCC cell lines, and could not identify any effect on rapalog sensitivity in in vitro culture assays. We conclude that mTOR pathway gene mutations did not contribute to rapalog resistance development in these six patients with advanced RCC. Furthermore, mechanisms of resistance to rapalogs in RCC remain unclear and our results suggest that PBRM1 loss may contribute to sensitivity through complex transcriptional effects.
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Antineoplásicos/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Renais/tratamento farmacológico , Proteínas Nucleares/genética , Inibidores de Proteínas Quinases/farmacologia , Fatores de Transcrição/genética , Adulto , Idoso , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Proteínas de Ligação a DNA , Progressão da Doença , Epigênese Genética , Everolimo/farmacologia , Everolimo/uso terapêutico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Heterogeneidade Genética/efeitos dos fármacos , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais/genética , Sirolimo/análogos & derivados , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Sequenciamento do ExomaRESUMO
BACKGROUND: Survival outcomes are poor for patients with metastatic urothelial carcinoma who receive standard, first-line, platinum-based chemotherapy. We assessed the overall survival of patients who received durvalumab (a PD-L1 inhibitor), with or without tremelimumab (a CTLA-4 inhibitor), as a first-line treatment for metastatic urothelial carcinoma. METHODS: DANUBE is an open-label, randomised, controlled, phase 3 trial in patients with untreated, unresectable, locally advanced or metastatic urothelial carcinoma, conducted at 224 academic research centres, hospitals, and oncology clinics in 23 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. We randomly assigned patients (1:1:1) to receive durvalumab monotherapy (1500 mg) administered intravenously every 4 weeks; durvalumab (1500 mg) plus tremelimumab (75 mg) administered intravenously every 4 weeks for up to four doses, followed by durvalumab maintenance (1500 mg) every 4 weeks; or standard-of-care chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin, depending on cisplatin eligibility) administered intravenously for up to six cycles. Randomisation was done through an interactive voice-web response system, with stratification by cisplatin eligibility, PD-L1 status, and presence or absence of liver metastases, lung metastases, or both. The coprimary endpoints were overall survival compared between the durvalumab monotherapy versus chemotherapy groups in the population of patients with high PD-L1 expression (the high PD-L1 population) and between the durvalumab plus tremelimumab versus chemotherapy groups in the intention-to-treat population (all randomly assigned patients). The study has completed enrolment and the final analysis of overall survival is reported. The trial is registered with ClinicalTrials.gov, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24. FINDINGS: Between Nov 24, 2015, and March 21, 2017, we randomly assigned 1032 patients to receive durvalumab (n=346), durvalumab plus tremelimumab (n=342), or chemotherapy (n=344). At data cutoff (Jan 27, 2020), median follow-up for survival was 41·2 months (IQR 37·9-43·2) for all patients. In the high PD-L1 population, median overall survival was 14·4 months (95% CI 10·4-17·3) in the durvalumab monotherapy group (n=209) versus 12·1 months (10·4-15·0) in the chemotherapy group (n=207; hazard ratio 0·89, 95% CI 0·71-1·11; p=0·30). In the intention-to-treat population, median overall survival was 15·1 months (13·1-18·0) in the durvalumab plus tremelimumab group versus 12·1 months (10·9-14·0) in the chemotherapy group (0·85, 95% CI 0·72-1·02; p=0·075). In the safety population, grade 3 or 4 treatment-related adverse events occurred in 47 (14%) of 345 patients in the durvalumab group, 93 (27%) of 340 patients in the durvalumab plus tremelimumab group, and in 188 (60%) of 313 patients in the chemotherapy group. The most common grade 3 or 4 treatment-related adverse event was increased lipase in the durvalumab group (seven [2%] of 345 patients) and in the durvalumab plus tremelimumab group (16 [5%] of 340 patients), and neutropenia in the chemotherapy group (66 [21%] of 313 patients). Serious treatment-related adverse events occurred in 30 (9%) of 345 patients in the durvalumab group, 78 (23%) of 340 patients in the durvalumab plus tremelimumab group, and 50 (16%) of 313 patients in the chemotherapy group. Deaths due to study drug toxicity were reported in two (1%) patients in the durvalumab group (acute hepatic failure and hepatitis), two (1%) patients in the durvalumab plus tremelimumab group (septic shock and pneumonitis), and one (<1%) patient in the chemotherapy group (acute kidney injury). INTERPRETATION: This study did not meet either of its coprimary endpoints. Further research to identify the patients with previously untreated metastatic urothelial carcinoma who benefit from treatment with immune checkpoint inhibitors, either alone or in combination regimens, is warranted. FUNDING: AstraZeneca.
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Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma/tratamento farmacológico , Inibidores de Checkpoint Imunológico/administração & dosagem , Neoplasias Urológicas/tratamento farmacológico , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma/mortalidade , Carcinoma/secundário , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Neoplasias Urológicas/mortalidade , Neoplasias Urológicas/patologia , Urotélio/efeitos dos fármacos , Urotélio/patologiaRESUMO
BACKGROUND: Testosterone suppression is the standard treatment for advanced prostate cancer, and it is associated with side-effects that impair patients' quality of life, like sexual dysfunction, osteoporosis, weight gain, and increased cardiovascular risk. We hypothesized that abiraterone acetate with prednisone (AAP) and apalutamide, alone or in combination, can be an effective hormonal therapy also possibly decreasing castration-associated side effects. METHODS: Phase II, open-label, randomized, efficacy trial of abiraterone acetate plus prednisone (AAP) and Androgen Deprivation Therapy (ADT) versus apalutamide versus the combination of AAP (without ADT) and apalutamide. Key eligibility criteria are confirmed prostate adenocarcinoma; biochemical relapse after definitive treatment (PSA ≥ 4 ng/ml and doubling time less than 10 months, or PSA ≥ 20 ng/ml); newly diagnosed locally advanced or metastatic prostate cancer; asymptomatic to moderately symptomatic regarding bone symptoms. Patients with other histology besides adenocarcinoma or previous use of hormonal therapy or chemotherapy were excluded. DISCUSSION: There is an urgent need to study and validate regimens such as new hormonal agents that may add benefit to castration with an acceptable safety profile. We aim to evaluate if apalutamide in monotherapy or in combination with AAP is an effective and safety hormonal treatment that can spare patients of androgen deprivation therapy. TRIAL REGISTRATION: This trial was registered in ClinicalTrials.gov on October 16, 2017, under Identifier: NCT02867020.
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Acetato de Abiraterona/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Antagonistas de Receptores de Andrógenos/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Gosserrelina/uso terapêutico , Prednisona/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Tioidantoínas/uso terapêutico , Acetato de Abiraterona/administração & dosagem , Antagonistas de Receptores de Andrógenos/administração & dosagem , Antineoplásicos Hormonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica , Intervalo Livre de Doença , Gosserrelina/administração & dosagem , Humanos , Masculino , Medidas de Resultados Relatados pelo Paciente , Prednisona/administração & dosagem , Qualidade de Vida , Testosterona/sangue , Tioidantoínas/administração & dosagem , Resultado do TratamentoRESUMO
INTRODUCTION: Gene-expression signatures for prognosis have been reported in localized renal cell carcinoma (RCC). The aim of this study was to test the predictive power of two different signatures, ClearCode34, a 34-gene signature model [Eur Urol 2014;66:77-84], and an 8-gene signature model [Eur Urol 2015;67:17-20], in the setting of systemic therapy for metastatic disease. MATERIALS AND METHODS: Metastatic RCC (mRCC) patients from five institutions who were part of TCGA were identified and clinical data were retrieved. We trained and implemented each gene model as described by the original study. The latter was demonstrated by faithful regeneration of a figure and results from the original study. mRCC patients were dichotomized to good or poor prognostic risk groups using each gene model. Cox proportional hazard regression and concordance index (C-Index) analysis were used to investigate an association between each prognostic risk model and overall survival (OS) from first-line therapy. RESULTS: Overall, 54 patients were included in the final analysis. The primary endpoint was OS. Applying the ClearCode34 model, median survival for the low-risk-ccA (n = 17)-and the high-risk-ccB (n = 37)-subtypes were 27.6 and 22.3 months (hazard ratio (HR): 2.33; p = .039), respectively. ClearCode34 ccA/ccB and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) classifications appear to represent distinct risk criteria in mRCC, and we observed no significant overlap in classification (p > .05, chi-square test). On multivariable analyses and adjusting for IMDC groups, ccB remained independently associated with a worse OS (p = .044); the joint model of ccA/ccB and IMDC was significantly more accurate in predicting OS than a model with IMDC alone (p = .045, F-test). This was also observed in C-Index analysis; a model with both ccA and ccB subtypes had higher accuracy (C-Index 0.63, 95% confidence interval [CI] = 0.51-0.75) and 95% CIs of the C-Index that did not include the null value of 0.5 in contrast to a model with IMDC alone (0.60, CI = 0.47-0.72). The 8-gene signature molecular subtype model was a weak but insignificant predictor of survival in this cohort (p = .13). A model that included both the 8-gene signature and IMDC (C-Index 0.62, CI = 0.49-0.76) was more prognostic than IMDC alone but did not reach significance, as the 95% CI included the null value of 0.5. These two genomic signatures share no genes in common and are enriched in different biological pathways. The ClearCode34 included genes ARNT and EPAS1 (also known as HIF2a), which are involved in regulation of gene expression by hypoxia-inducible factor. CONCLUSION: The ClearCode34 but not the 8-gene molecular model improved the prognostic predictive power of the IMDC model in this cohort of 54 patients with metastatic clear cell RCC. The Oncologist 2017;22:286-292 IMPLICATIONS FOR PRACTICE: The clinical and laboratory factors included in the International Metastatic Renal Cell Carcinoma Database Consortium model provide prognostic information in metastatic renal cell carcinoma (mRCC). The present study shows that genomic signatures, originally validated in localized RCC, may add further complementary prognostic information in the metastatic setting. This study may provide new insights into the molecular basis of certain mRCC subgroups. The integration of clinical and molecular data has the potential to redefine mRCC classification, enhance the understanding of mRCC biology, and potentially predict response to treatment in the future.
Assuntos
Carcinoma de Células Renais/genética , Terapia de Alvo Molecular , Segunda Neoplasia Primária/genética , Prognóstico , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinoma de Células Renais/classificação , Carcinoma de Células Renais/patologia , Estudos de Coortes , Bases de Dados Factuais , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Segunda Neoplasia Primária/patologia , Fatores de RiscoRESUMO
BACKGROUND: Vascular endothelial growth factor (VEGF)-targeted therapies are standard treatment for metastatic renal cell carcinoma (mRCC); however, toxicities can lead to drug discontinuation, which can affect patient outcomes. This study was aimed at identifying risk factors for toxicity and constructing the first model to predict toxicity-related treatment discontinuation (TrTD) in mRCC patients treated with VEGF-targeted therapies. METHODS: The baseline characteristics, treatment outcomes, and toxicity data were collected for 936 mRCC patients receiving first-line VEGF-targeted therapy from the International Metastatic Renal Cell Carcinoma Database Consortium. A competing risk regression model was used to identify risk factors for TrTD, and it accounted for other causes as competing risks. RESULTS: Overall, 198 (23.8%) experienced TrTD. Sunitinib was the most common VEGF-targeted therapy (77%), and it was followed by sorafenib (18.4%). The median time on therapy was 7.1 months for all patients and 4.4 months for patients with TrTD. The most common toxicities leading to TrTD included fatigue, diarrhea, and mucositis. In a multivariate analysis, significant predictors for TrTD were a baseline age ≥60 years, a glomerular filtration rate (GFR) <30 mL/min/1.73 m(2) , a single metastatic site, and a sodium level <135 mmol/L. A risk group model was developed that used the number of patient risk factors to predict the risk of TrTD. CONCLUSIONS: In the largest series to date, age, GFR, number of metastatic sites, and baseline sodium level were found to be independent risk factors for TrTD in mRCC patients receiving VEGF-targeted therapy. Based on the number of risk factors present, a model for predicting TrTD was built to be used as a tool for toxicity monitoring in clinical practice.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Modelos Estatísticos , Terapia de Alvo Molecular/efeitos adversos , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Axitinibe , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/secundário , Bases de Dados Factuais , Diarreia/induzido quimicamente , Esquema de Medicação , Fadiga/induzido quimicamente , Feminino , Síndrome Mão-Pé/etiologia , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Indazóis/administração & dosagem , Indazóis/efeitos adversos , Indóis/administração & dosagem , Indóis/efeitos adversos , Estimativa de Kaplan-Meier , Neoplasias Renais/sangue , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Mucosite/induzido quimicamente , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Valor Preditivo dos Testes , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Sorafenibe , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , SunitinibeRESUMO
BACKGROUND: Tumour expression of selected microRNAs (miRs) correlates with cisplatin efficacy in multiple cancers. We investigated the role of selected miRs in patients receiving cisplatin-based therapy for advanced urothelial carcinoma (UC). METHODS: RNA was extracted from formalin-fixed paraffin-embedded tumour from 83 advanced UC patients who received cisplatin. A miR panel based on relevance for platinum sensitivity and UC was studied by quantitative reverse transcription quantitative PCR (RT-qPCR). Association of progression-free survival (PFS) with miR expression was analysed using cox regression. Selected TFs were chosen by association with the panel of miRs using the Transcription Regulation algorithm (GeneGo MetaCore+MetaDrug version 6.23 build 67496). Bladder cancer (BC) cell lines were used to investigate the previously described role of miR-21 mediating cisplatin sensitivity. RESULTS: The 83 patients had a median PFS of 8 months. In multivariate analysis, higher levels of E2F1 (P=0.01, HR: 1.95 (1.14, 3.33)), miR-21 (P=0.01, HR: 2.01 (1.17, 3.45)) and miR-372 (P=0.05, HR: 1.70 (1.00, 2.89)) were associated with a shorter PFS. In the 8 BC cell lines, miR-21 was not shown to be necessary nor sufficient for modulating cisplatin sensitivity. CONCLUSIONS: In metastatic UC patients treated with cisplatin-based therapy, high primary tumour levels of E2F1, miR-21 and miR-372 are associated with poor PFS independent of clinical prognostic factors. The in vitro study could not confirm miR-21 levels role in modulating platinum sensitivity.
Assuntos
Carcinoma/tratamento farmacológico , Carcinoma/genética , MicroRNAs/genética , Compostos Organoplatínicos/uso terapêutico , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/genética , Linhagem Celular , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Intervalo Livre de Doença , Células HEK293 , Humanos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genéticaRESUMO
Advances in next-generation sequencing have provided a unique opportunity to understand the biology of disease and mechanisms of sensitivity or resistance to specific agents. Renal cell carcinoma (RCC) is a heterogeneous disease and highly variable clinical responses have been observed with vascular endothelial growth factor (VEGF)-targeted therapy (VEGF-TT). We hypothesized that whole-exome sequencing analysis might identify genotypes associated with extreme response or resistance to VEGF-TT in metastatic (mRCC). Patients with mRCC who had received first-line sunitinib or pazopanib and were in 2 extreme phenotypes of response were identified. Extreme responders (ERs) were defined as those with partial response or complete response for 3 or more years (n=13) and primary refractory patients (PRPs) were defined as those with progressive disease within the first 3 months of therapy (n=14). International Metastatic RCC Database Consortium prognostic scores were not significantly different between the groups (P=.67). Considering the genes known to be mutated in RCC at significant frequency, PBRM1 mutations were identified in 7 ERs (54%) versus 1 PRP (7%) (P=.01). In addition, mutations in TP53 (n=4) were found only in PRPs (P=.09). Our data suggest that mutations in some genes in RCC may impact response to VEGF-TT.
Assuntos
Carcinoma de Células Renais/genética , Exoma/genética , Neoplasias Renais/genética , Fator A de Crescimento do Endotélio Vascular/genética , Carcinoma de Células Renais/tratamento farmacológico , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Fenótipo , PrognósticoRESUMO
Vascular endothelial growth factor (VEGF)-targeted agents are standard therapies for metastatic renal cell carcinoma (mRCC), associated with variable tumor shrinkage. Response Evaluation Criteria in Solid Tumors (RECIST) is of limited utility in this setting, and other imaging changes are sought to reliably predict outcome early. We aim to validate 10% tumor shrinkage as the best early indicator of outcome. Methods. In this institutional review board-approved, Health Insurance Portability and Accountability Act-compliant study, 66 mRCC patients with 165 lesions on clinical trials of VEGF-targeted agents underwent thoracic and abdominal computed tomography at baseline and at first follow-up after therapy. Measurements were performed according to RECIST and tumor shrinkage of ≥10% decrease in sum of the longest diameter (-10%SLD). Correlation with time-to-treatment failure (TTF) and overall survival (OS) were compared and stratified by response to the radiologic criteria. Receiver-operating characteristics (ROC) analysis yielded the optimal threshold change in SLD, defining patients with prolonged survival. Results. More than -10%SLD significantly differentiated responders from nonresponders (median TTF 8.4 vs. 4.1 months, p = .001), whereas partial response by RECIST did not (median TTF 6.9 vs. 5.5 months in responders vs. nonresponders, p = .34). -10%SLD was also significantly predictive of OS (median OS 35.1 vs. 15.0 months in responders vs. nonresponders, p = .003). ROC curve analysis yielded -9.3% in SLD as the optimal threshold for response/no response. Conclusion. Ten percent tumor shrinkage is validated as a reliable early predictor of outcome in mRCC patients receiving VEGF-targeted therapies and may provide a practical measure to guide therapeutic decisions.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/mortalidade , Feminino , Humanos , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Curva ROC , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
BACKGROUND: Based on improved clinical outcomes in randomized controlled clinical trials (RCTs) the FDA and EMA have approved bevacizumab with interferon, sunitinib, and pazopanib in the first-line treatment of low to intermediate risk metastatic clear cell renal cell carcinoma (mRCC). However, there is little comparative data to help in choosing the most effective drug among these agents. METHODS: We performed an indirect comparative effectiveness analysis of the pivotal RCTs of bevacizumab with interferon, sunitinib, or pazopanib compared to one another or interferon alone in first-line treatment of metastatic or advanced RCC. Endpoints of interest were overall survival (OS), progression free survival (PFS), and response rate (RR). Adverse events were also examined. RESULTS: The meta-estimate of the hazard ratio (95% confidence interval) for OS for bevacizumab with interferon vs. interferon alone was 0.86 (0.76-0.97), for sunitinib vs. interferon alone was 0.82 (0.67-1.00), for pazopanib vs. interferon alone was 0.74 (0.57-0.97), for sunitinib vs. bevacizumab with interferon was 0.95 (0.75-1.20), for pazopanib vs. bevacizumab with interferon was 0.86 (0.64-1.16), and for pazopanib vs. sunitinib was 0.91 (0.76-1.08). Similarly, bevacizumab with interferon, sunitinib, or pazopanib had better PFS and RR than interferon alone. Sunitinib and pazopanib had better RR than bevacizumab with interferon and there was suggestive evidence pazopanib may outperform sunitinib in terms of RR. CONCLUSIONS: Bevacizumab with interferon, sunitinib, and pazopanib are adequate first-line options in treatment of mRCC. Interferon alone should not be considered an optimal first-line treatment.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Metástase Neoplásica/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Humanos , Indazóis , Indóis/uso terapêutico , Interferons/uso terapêutico , Terapia de Alvo Molecular , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Sulfonamidas/uso terapêutico , Sunitinibe , Análise de SobrevidaRESUMO
BACKGROUND: Treatment of metastatic clear cell renal carcinoma (mccRCC) has changed dramatically over the past 20 years, without improvement in the development of biomarkers. Recently, circulating tumor cells (CTCs) have been validated as a prognostic and predictive tool for many solid tumors. OBJECTIVE: We evaluated CTCs in blood samples obtained from patients diagnosed with mccRCC. Comparisons of CTC counts, protein expression profiling, and DNA mutants were made in relation to overall survival and progression-free survival. METHODS: CTCs were isolated from 10 mL blood samples using the ISET® system (Isolation by SizE of Tumor Cells; Rarecells, France) and counted. Protein expression was evaluated in immunocytochemistry assays. DNA mutations were identified with next generation sequencing (NGS). RESULTS: Blood samples (10 mL) were collected from 12 patients with mccRCC before the start of first-line systemic therapy, and again 30 and 60 days after the start of treatment. All 12 patients had CTCs detected at baseline (median, 1.5 CTCs/mL; range: 0.25-7.75). Patients with CTC counts greater than the median had two or more metastatic sites and exhibited worse progression-free survival (19.7 months) compared to those with CTC counts less than the median (31.1 months). Disease progression was observed in 7/12 patients during the study. Five of these patients had baseline CTC counts greater than the median, one had higher CTC levels at the second blood collection, and one patient had CTCs present at 1 CTC/mL which positively stained for PD-L1, N-cadherin, VEGF, and SETD2. CTC DNA from six patients with worse outcomes was subjected to NGS. However, no conclusions could be made due to the low variant allele frequencies. CONCLUSION: Detection of CTCs in patients with mccRCC receiving first-line treatment is a feasible tool with prognostic potential since increased numbers of CTCs were found to be associated with metastasis and disease progression.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Células Neoplásicas Circulantes , Humanos , Células Neoplásicas Circulantes/patologia , Prognóstico , Carcinoma de Células Renais/genética , Imuno-Histoquímica , Progressão da Doença , Neoplasias Renais/genética , Genômica , DNA , Biomarcadores TumoraisRESUMO
BACKGROUND: Systemic treatment with immune combinations is the gold standard for metastatic renal cell carcinoma (mRCC) worldwide. The systemic immune-inflammation index (SII) is a prognostic marker for several types of malignant neoplasms, including mRCC, in the era of tyrosine kinase inhibitor (TKI) treatment. Data regarding the prognostic value of the SII in patients with mRCC treated with immunotherapy are scarce and controversial.⯠METHODS: We retrospectively collected the data of patients with mRCC from 56 centers in 18 countries. SII (Platelet × Neutrophil/Lymphocyte count) was calculated prior to the first systemic treatment and cut-off was defined by a survival receiver operating characteristic (ROC) analysis. The primary objective of our retrospective study was to assess the outcomes of patients treated with first-line immunotherapy.⯠RESULTS: Data from 1034 mRCC patients was collected and included in this analysis. The SII cut-off value was 1265. After a follow-up of 26.7 months, and the overall survival (OS) and progression-free survival (PFS) were 39.8 and 15.7 months, respectively. According to SII (low vs. high), patients with low-SII had longer OS (55.7 vs. 22.2 months, P < .001), better PFS (20.8 vs. 8.5 months, P < .001), and higher overall response rate (52 vs. 37%, P = .033). CONCLUSION: A high SII is associated with poor oncological outcomes in patients with mRCC. SII could be an easily accessible prognostic indicator for use in clinical practice.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/patologia , Estudos Retrospectivos , Neoplasias Renais/patologia , Análise de Sobrevida , Prognóstico , Inflamação/patologiaRESUMO
BACKGROUND AND OBJECTIVE: Recent clinical trials have shown improvement in progression-free survival in men with metastatic prostate cancer (mPC) treated with combination poly-ADP ribose polymerase (PARP) inhibitors (PARPi) and novel hormonal therapy (NHT). Regulatory bodies in the USA, Canada, Europe, and Japan have recently approved this combination therapy for mPC. Common adverse events (AEs) include fatigue, nausea and vomiting, and anemia. Nuanced AE management guidance for these combinations is lacking. The panel objective was to develop expert consensus on AE management in patients with mPC treated with the combination PARPi + NHT. METHODS: The RAND/University of California Los Angeles modified Delphi Panel method was used. AEs were defined using the Common Terminology Criteria for Adverse Events. Twelve experts (seven medical oncologists, one advanced practice registered nurse, three urologists, and one patient advocate) reviewed the relevant literature; independently rated initial AE management options for the agent suspected of causing the AE for 419 patient scenarios on a 1-9 scale; discussed areas of agreement (AoAs) and disagreement (AoDs) at a March 2023 meeting; and repeated these ratings following the meeting. Second-round ratings formed the basis of guidelines. KEY FINDINGS AND LIMITATIONS: AoDs decreased from 41% to 21% between the first and second round ratings, with agreement on at least one management strategy for every AE. AoAs included the following: (1) continue therapy with symptomatic treatment for patients with mild AEs; (2) for moderate fatigue, recommend nonpharmacologic treatment, hold treatment temporarily, and restart at a reduced dose when symptoms resolve; (3) for severe nausea or any degree of vomiting where symptomatic treatment fails, hold treatment temporarily and restart at a reduced dose when symptoms resolve; and (4) for hemoglobin 7.1-8.0 g/dl and symptoms of anemia, hold treatment temporarily and restart at a reduced dose after red blood cell transfusion. CONCLUSIONS AND CLINICAL IMPLICATIONS: This expert guidance can support management of AEs in patients with mPC receiving combination PARPi + NHT therapy. PATIENT SUMMARY: A panel of experts developed guidelines for adverse event (AE) management in patients with metastatic prostate cancer treated with a combination of poly-ADP ribose polymerase inhibitors and novel hormonal therapy. For mild AEs, continuation of cancer therapy along with symptomatic treatment is recommended. For moderate or severe AEs, cancer therapy should be stopped temporarily and restarted at the same or a reduced dose when AE resolves.