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1.
Ceska Gynekol ; 86(1): 54-60, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33752410

RESUMO

OBJECTIVE: An evaluation of the safety of poly-ADP-ribose-polymerase inhibitors (PARPi) in ovarian cancer treatment. METHODS: An analysis of the studies on PARP inhibitors, a summary of the most common and serious adverse events. RESULTS: According to the studies, the most common adverse events of PARPi include hematotoxicity, nausea and vomiting. Serious adverse events leading to dose reduction or treatment interruption or termination include anemia, thrombocytopenia, nausea, fatigue and hypertension. CONCLUSION: According to the results of the recent studies, the treatment of ovarian cancer with PARP inhibitors is generally safe.


Assuntos
Neoplasias Ovarianas , Inibidores de Poli(ADP-Ribose) Polimerases , Carcinoma Epitelial do Ovário , Feminino , Humanos , Náusea , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Vômito
2.
Ann Oncol ; 32(4): 512-521, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33453391

RESUMO

BACKGROUND: This study evaluated maintenance treatment with niraparib, a potent inhibitor of poly(ADP-ribose) polymerase 1/2, in patients with platinum-sensitive recurrent ovarian cancer. PATIENTS AND METHODS: In this phase III, double-blind, placebo-controlled study conducted at 30 centers in China, adults with platinum-sensitive recurrent ovarian cancer who had responded to their most recent platinum-containing chemotherapy were randomized 2 : 1 to receive oral niraparib (300 mg/day) or matched placebo until disease progression or unacceptable toxicity (NCT03705156). Following a protocol amendment, patients with a bodyweight <77 kg or a platelet count <150 × 103/µl received 200 mg/day, and all other patients 300 mg/day, as an individualized starting dose (ISD). Randomization was carried out by an interactive web response system and stratified by BRCA mutation, time to recurrence following penultimate chemotherapy, and response to most recent chemotherapy. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review. RESULTS: Between 26 September 2017 and 2 February 2019, 265 patients were randomized to receive niraparib (n = 177) or placebo (n = 88); 249 patients received an ISD (300 mg, n = 14; 200 mg, n = 235) as per protocol. In the intention-to-treat population, median PFS was significantly longer for patients receiving niraparib versus placebo: 18.3 [95% confidence interval (CI), 10.9-not evaluable] versus 5.4 (95% CI, 3.7-5.7) months [hazard ratio (HR) = 0.32; 95% CI, 0.23-0.45; P < 0.0001], and a similar PFS benefit was observed in patients receiving an ISD, regardless of BRCA mutation status. Grade ≥3 treatment-emergent adverse events occurred in 50.8% and 19.3% of patients who received niraparib and placebo, respectively; the most common events were neutrophil count decreased (20.3% versus 8.0%) and anemia (14.7% versus 2.3%). CONCLUSIONS: Niraparib maintenance treatment reduced the risk of disease progression or death by 68% and prolonged PFS compared to placebo in patients with platinum-sensitive recurrent ovarian cancer. Individualized niraparib dosing is effective and safe and should be considered standard practice in this setting.


Assuntos
Neoplasias Ovarianas , Inibidores de Poli(ADP-Ribose) Polimerases , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica , China , Método Duplo-Cego , Feminino , Humanos , Indazóis , Quimioterapia de Manutenção , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Piperidinas , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos
3.
Anticancer Res ; 41(2): 551-556, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33517260

RESUMO

Treatment of metastatic prostate cancer has evolved significantly over the past decade. Palliative therapy has, historically, consisted of androgen deprivation, chemotherapy and different radiation therapy approaches. More recently, breakthrough therapy with the use of poly-ADP-ribose polymerase (PARP) inhibitors has led to significant improvement in the outcome of patients with metastatic prostate cancer who harbor certain genetic mutations. This concise review focuses on the 3 PARP inhibitors that have shown activity in metastatic prostate cancer.


Assuntos
Indazóis/uso terapêutico , Indóis/uso terapêutico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Piperidinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Animais , Proteína BRCA1/genética , Proteína BRCA2/genética , Predisposição Genética para Doença , Humanos , Indazóis/efeitos adversos , Indóis/efeitos adversos , Masculino , Mutação , Metástase Neoplásica , PTEN Fosfo-Hidrolase/genética , Fenótipo , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Piperidinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Resultado do Tratamento
4.
Lancet Haematol ; 8(2): e122-e134, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33347814

RESUMO

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors have shown efficacy and acceptable safety in a range of neoplasms, particularly in ovarian cancers. However, some concerns have emerged regarding rare and delayed adverse events including cases of myelodysplastic syndrome and acute myeloid leukaemia, for which data are scarce. The aim of this study was to estimate the risk of myelodysplastic syndrome and acute myeloid leukaemia related to PARP inhibitors, via a systematic review and safety meta-analysis, and to describe clinical features of PARP inhibitor-related myelodysplastic syndrome and acute myeloid leukaemia cases reported in WHO's pharmacovigilance database (VigiBase). METHODS: We systematically reviewed randomised controlled trials (RCTs) comparing PARP inhibitor therapy versus control treatments (placebo and non-placebo) in adults (age ≥18 years) treated for cancer in MEDLINE, the Cochrane Central Register of Controlled Trials, and the ClinicalTrials.gov registry with ongoing surveillance up to May 31, 2020. The date range for included studies was not restricted. By a stepwise method to capture all available adverse events, we first extracted data on myelodysplastic syndrome and acute myeloid leukaemia cases from ClinicalTrials.gov. If cases were not available, we extracted them from published manuscripts, or subsequently contacted corresponding authors or sponsors to provide data. RCTs without available data from ClinicalTrials.gov, publications, or corresponding authors or sponsors were excluded. The primary outcome was the summary risk of myelodysplastic syndrome and acute myeloid leukaemia related to PARP inhibition versus placebo treatment in RCTs. We used a fixed-effects meta-analysis to obtain Peto odds ratios (ORs) with 95% CIs. In a separate observational, retrospective, cross-sectional pharmacovigilance study of VigiBase, cases of myelodysplastic syndrome and acute myeloid leukaemia related to PARP inhibitor therapy were extracted on May 3, 2020, and clinical features summarised with a focus on median duration of PARP inhibitor exposure, median latency period between first drug exposure and diagnosis, and proportion of cases resulting in death. Our systematic review and safety meta-analysis were registered with PROSPERO, CRD42020175050. Our retrospective pharmacovigilance study was registered on ClinicalTrials.gov, NCT04326023. FINDINGS: For our safety meta-analysis, initial searches identified 1617 citations, and 31 RCTs were systematically reviewed for eligibility. 28 RCTs with available adverse events were analysed (18 placebo and ten non-placebo RCTs), with 5693 patients in PARP inhibitor groups and 3406 patients in control groups. Based on the 18 placebo RCTs (n=7307 patients), PARP inhibitors significantly increased the risk of myelodysplastic syndrome and acute myeloid leukaemia compared with placebo treatment (Peto OR 2·63 [95% CI 1·13-6·14], p=0·026) with no between-study heterogeneity (I2=0%, χ2 p=0·91). The incidence of myelodysplastic syndrome and acute myeloid leukaemia across PARP inhibitor groups was 0·73% (95% CI 0·50-1·07; I2=0%, χ2 p=0·87; 21 events out of 4533 patients) and across placebo groups was 0·47% (0·26-0·85; I2=0%, χ2 p=1·00; three events out of 2774 patients). All 28 RCTs were rated as having unclear risk of bias. In VigiBase, 178 cases of myelodysplastic syndrome (n=99) and acute myeloid leukaemia (n=79) related to PARP inhibitor therapy were extracted. In cases with available data, median treatment duration was 9·8 months (IQR 3·6-17·4; n=96) and median latency period since first exposure to a PARP inhibitor was 17·8 months (8·4-29·2; n=58). Of 104 cases that reported outcomes, 47 (45%) resulted in death. INTERPRETATION: PARP inhibitors increased the risk of myelodysplastic syndrome and acute myeloid leukaemia versus placebo treatment. These delayed and often lethal adverse events should be studied further to improve clinical understanding, particularly in the front-line maintenance setting. FUNDING: None.


Assuntos
Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Razão de Chances , Efeito Placebo , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Trombocitopenia/etiologia , Resultado do Tratamento
5.
Medicine (Baltimore) ; 99(45): e23040, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33157956

RESUMO

BACKGROUND: There search of PARP inhibitors has made great breakthroughs and progress. Become a new type of medicine for cancer treatment,bringing hope to more advanced cancer patients.The purpose of this systematic review is to evaluate the clinical efficacy and adverse effects of PARP inhibitorscombined with chemotherapy and chemotherapy alone in the treatment of cancer patients. METHODS: We searched the following 4 databases, including: PubMed, EMBASE, Web of Science, and Cochrane Library. The search will also be conducted at the clinical trial centers: ClinicalTrials.gov, ISRCTN Registry, WHO International Clinical Trials Registration Platform. The search date is as of September 22, 2020. There is no language restriction during this search, and the latest documents are kept updated through settings. The subject search terms were identified as "PARP Inhibitor", "Neoplasms" and "Dug therapy". The Phase 2 and Phase 3 clinical trials comparing PARP inhibitor combined with chemotherapy and chemotherapy alone were included. The results include overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and adverse events. Two researchers separately completed the article inclusion, data extraction and quality evaluation of this study. The assessment of the risk of bias and data will be conducted using Review Manager. ETHICS AND DISSEMINATION: All articles are published and do not require the approval of the ethics committee and the signed informed consent form. The results of this systematic review will be published through peer-reviewed publications. REGISTERED: Registered on INPLASY and the registration number is INPLASY202090087.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Adulto , Idoso , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Gerenciamento de Dados , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/mortalidade , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Intervalo Livre de Progressão , Resultado do Tratamento
7.
Am J Respir Cell Mol Biol ; 63(5): 571-590, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32640172

RESUMO

PARP1, the major isoform of a family of ADP-ribosylating enzymes, has been implicated in the regulation of various biological processes including DNA repair, gene transcription, and cell death. The concept that PARP1 becomes activated in acute lung injury (ALI) and that pharmacological inhibition or genetic deletion of this enzyme can provide therapeutic benefits emerged over 20 years ago. The current article provides an overview of the cellular mechanisms involved in the pathogenetic roles of PARP1 in ALI and provides an overview of the preclinical data supporting the efficacy of PARP (poly[ADP-ribose] polymerase) inhibitors. In recent years, several ultrapotent PARP inhibitors have been approved for clinical use (for the therapy of various oncological diseases): these newly-approved PARP inhibitors were recently reported to show efficacy in animal models of ALI. These observations offer the possibility of therapeutic repurposing of these inhibitors for patients with ALI. The current article lays out a potential roadmap for such repurposing efforts. In addition, the article also overviews the scientific basis of potentially applying PARP inhibitors for the experimental therapy of viral ALI, such as coronavirus disease (COVID-19)-associated ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pulmão/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Lesão Pulmonar Aguda/enzimologia , Lesão Pulmonar Aguda/virologia , Animais , Antivirais/efeitos adversos , Betacoronavirus/patogenicidade , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/virologia , Interações Hospedeiro-Patógeno , Humanos , Pulmão/enzimologia , Pulmão/virologia , Pandemias , Pneumonia Viral/enzimologia , Pneumonia Viral/virologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Transdução de Sinais/efeitos dos fármacos
8.
Eur J Cancer ; 136: 1-3, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32610172
9.
Lancet Oncol ; 21(5): 710-722, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32359490

RESUMO

BACKGROUND: In ARIEL3, rucaparib maintenance treatment significantly improved progression-free survival versus placebo. Here, we report prespecified, investigator-assessed, exploratory post-progression endpoints and updated safety data. METHODS: In this ongoing (enrolment complete) randomised, placebo-controlled, phase 3 trial, patients aged 18 years or older who had platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least two previous platinum-based chemotherapy regimens and responded to their last platinum-based regimen were randomly assigned (2:1) to oral rucaparib (600 mg twice daily) or placebo in 28-day cycles using a computer-generated sequence (block size of six with stratification based on homologous recombination repair gene mutation status, progression-free interval following penultimate platinum-based regimen, and best response to most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary endpoint of investigator-assessed progression-free survival has been previously reported. Prespecified, exploratory outcomes of chemotherapy-free interval (CFI), time to start of first subsequent therapy (TFST), time to disease progression on subsequent therapy or death (PFS2), and time to start of second subsequent therapy (TSST) and updated safety were analysed (visit cutoff Dec 31, 2017). Efficacy analyses were done in all patients randomised to three nested cohorts: patients with BRCA mutations, patients with homologous recombination deficiencies, and the intention-to-treat population. Safety analyses included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT01968213. FINDINGS: Between April 7, 2014, and July 19, 2016, 564 patients were enrolled and randomly assigned to rucaparib (n=375) or placebo (n=189). Median follow-up was 28·1 months (IQR 22·0-33·6). In the intention-to-treat population, median CFI was 14·3 months (95% CI 13·0-17·4) in the rucaparib group versus 8·8 months (8·0-10·3) in the placebo group (hazard ratio [HR] 0·43 [95% CI 0·35-0·53]; p<0·0001), median TFST was 12·4 months (11·1-15·2) versus 7·2 months (6·4-8·6; HR 0·43 [0·35-0·52]; p<0·0001), median PFS2 was 21·0 months (18·9-23·6) versus 16·5 months (15·2-18·4; HR 0·66 [0·53-0·82]; p=0·0002), and median TSST was 22·4 months (19·1-24·5) versus 17·3 months (14·9-19·4; HR 0·68 [0·54-0·85]; p=0·0007). CFI, TFST, PFS2, and TSST were also significantly longer with rucaparib than placebo in the BRCA-mutant and homologous recombination-deficient cohorts. The most frequent treatment-emergent adverse event of grade 3 or higher was anaemia or decreased haemoglobin (80 [22%] patients in the rucaparib group vs one [1%] patient in the placebo group). Serious treatment-emergent adverse events were reported in 83 (22%) patients in the rucaparib group and 20 (11%) patients in the placebo group. Two treatment-related deaths have been previously reported in this trial; there were no new treatment-related deaths. INTERPRETATION: In these exploratory analyses over a median follow-up of more than 2 years, rucaparib maintenance treatment led to a clinically meaningful delay in starting subsequent therapy and provided lasting clinical benefits versus placebo in all three analysis cohorts. Updated safety data were consistent with previous reports. FUNDING: Clovis Oncology.


Assuntos
Carcinoma/tratamento farmacológico , Indóis/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma/patologia , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Indóis/efeitos adversos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/patologia , Platina/administração & dosagem , Platina/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de Progressão , Resultado do Tratamento
10.
N Engl J Med ; 382(22): 2091-2102, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32343890

RESUMO

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 , Genes BRCA1 , Genes BRCA2 , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , 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/patologia
11.
BMC Cancer ; 20(1): 215, 2020 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-32171277

RESUMO

BACKGROUND: Poly (ADP-ribose) polymerase (PARP) inhibitors are approved for the treatment of breast cancer susceptibility genes 1 and 2 (BRCA1/2) mutant ovarian and breast cancers, and are now being evaluated in metastatic castration-resistant prostate cancer (mCRPC). Reversion mutations that restore BRCA1/2 function have been shown to be responsible for resistance to platinum-based chemotherapy and PARP inhibitors, however there is no information on the sequential use of these agents in prostate cancer. CASE PRESENTATION: A patient with mCRPC associated with a germline BRCA2 mutation was sequentially treated with carboplatin and the PARP inhibitor rucaparib. Genomic profiling of the available baseline tumor and progression blood samples using next-generation sequencing panel tests identified polyclonal BRCA2 reversion mutations post carboplatin treatment but prior to rucaparib treatment. A total of 12 somatic reversion mutations were detected and ranged from small indels to larger deletions of up to 387 amino acids. These alterations are all predicted to restore the BRCA2 open reading frame and potentially protein function. The patient received limited benefit while on rucaparib, likely due to these reversion mutations observed prior to treatment. CONCLUSIONS: Here we report a case of a patient with prostate cancer who received a platinum agent and PARP inhibitor sequentially and in whom polyclonal BRCA2 reversion mutations were identified as the likely mechanism of acquired resistance to carboplatin and primary resistance to PARP inhibition. These findings suggest caution is warranted in sequencing these agents.


Assuntos
Proteína BRCA2/genética , Carboplatina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Genes BRCA2 , Mutação em Linhagem Germinativa/efeitos dos fármacos , Indóis/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Carboplatina/efeitos adversos , Humanos , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Resultado do Tratamento
12.
Gynecol Oncol ; 157(2): 500-507, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32173049

RESUMO

BACKGROUND: Olaparib was approved on December 19, 2014 by the US FDA as 4th-line therapy (and beyond) for patients with germline BRCA1/2 mutations; rucaparib was approved on December 19, 2016 as 3rd-line therapy (and beyond) for germline or somatic BRCA1/2-mutated recurrent disease. On October 23, 2019, niraparib was approved for treatment of women with damaging mutations in BRCA1/2 or other homologous recombination repair genes who had been treated with three or more prior regimens. We compared the cost-effectiveness of PARPi(s) with intravenous regimens for platinum-resistant disease. METHODS: Median progression-free survival (PFS) and toxicity data from regulatory trials were incorporated in a model which transitioned patients through response, hematologic complications, non-hematologic complications, progression, and death. Using TreeAge Pro 2017, each PARPi(s) was compared separately to non­platinum-based and bevacizumab-containing regimens. Costs of IV drugs, managing toxicities, infusions, and supportive care were estimated using 2017 Medicare data. Incremental cost-effectiveness ratios (ICERs) were calculated and PFS was reported in quality adjusted life months for platinum-resistant populations. RESULTS: Non­platinum-based intravenous chemotherapy was most cost effective ($6,412/PFS-month) compared with bevacizumab-containing regimens ($12,187/PFS-month), niraparib ($18,970/PFS-month), olaparib ($16,327/PFS-month), and rucaparib ($16,637/PFS-month). ICERs for PARPi(s) were 3-3.5× times greater than intravenous non­platinum-based regimens. CONCLUSION: High costs of orally administered PARPi(s) were not mitigated or balanced by costs of infusion and managing toxicities of intravenous regimens typically associated with lower response and shorter median PFS. Balancing modest clinical benefit with costs of novel therapies remains problematic and could widen disparities among those with limited access to care.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/economia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/economia , Administração Oral , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Bevacizumab/economia , Carcinoma Epitelial do Ovário/economia , Análise Custo-Benefício , Custos de Medicamentos , Feminino , Humanos , Indazóis/administração & dosagem , Indazóis/efeitos adversos , Indazóis/economia , Indóis/administração & dosagem , Indóis/efeitos adversos , Indóis/economia , Infusões Intravenosas , Cadeias de Markov , Modelos Estatísticos , Recidiva Local de Neoplasia/economia , Neoplasias Ovarianas/economia , Ftalazinas/administração & dosagem , Ftalazinas/efeitos adversos , Ftalazinas/economia , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Piperazinas/economia , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Piperidinas/economia , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Qualidade de Vida , Estados Unidos
13.
Sci Rep ; 10(1): 2585, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066817

RESUMO

Polypharmacology plays an important role in defining response and adverse effects of drugs. For some mechanisms, experimentally mapping polypharmacology is commonplace, although this is typically done within the same protein class. Four PARP inhibitors have been approved by the FDA as cancer therapeutics, yet a precise mechanistic rationale to guide clinicians on which to choose for a particular patient is lacking. The four drugs have largely similar PARP family inhibition profiles, but several differences at the molecular and clinical level have been reported that remain poorly understood. Here, we report the first comprehensive characterization of the off-target kinase landscape of four FDA-approved PARP drugs. We demonstrate that all four PARP inhibitors have a unique polypharmacological profile across the kinome. Niraparib and rucaparib inhibit DYRK1s, CDK16 and PIM3 at clinically achievable, submicromolar concentrations. These kinases represent the most potently inhibited off-targets of PARP inhibitors identified to date and should be investigated further to clarify their potential implications for efficacy and safety in the clinic. Moreover, broad kinome profiling is recommended for the development of PARP inhibitors as PARP-kinase polypharmacology could potentially be exploited to modulate efficacy and side-effect profiles.


Assuntos
Antineoplásicos/química , Indazóis/química , Indóis/química , Ftalazinas/química , Piperazinas/química , Piperidinas/química , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/química , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Sítios de Ligação , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Células HEK293 , Humanos , Indazóis/administração & dosagem , Indazóis/efeitos adversos , Indóis/administração & dosagem , Indóis/efeitos adversos , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/patologia , Ftalazinas/administração & dosagem , Ftalazinas/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Polifarmacologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Especificidade por Substrato
14.
Support Care Cancer ; 28(5): 2435-2442, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32048043

RESUMO

Olaparib is the first poly(ADP-ribose) polymerase inhibitor approved as maintenance therapy of recurrent ovarian cancer (OC) patients with a BRCA mutation. To achieve the maximum clinical benefit, adherence to olaparib must be persistent. However, in clinical practice, this is challenged by the frequent suboptimal management of toxicities. In view of the expanding use of olaparib also in Italy, physicians must learn how to adequately and promptly manage drug toxicities not to unnecessarily interrupt or reduce the dose. The experts agreed that nausea,vomiting, anemia, and fatigue are the most frequent events experienced by OC patients on olaparib, and that these toxicities usually develop early during treatment, are mainly of grade 1-2 and transient and can be managed with simple non-pharmacological interventions. By sharing their real-world experiences, the panel prepared, for each toxicity, an algorithm organized by grade and besides the procedures indicated in the local label, included supportive care interventions based also on nutritional and lifestyle modifications and psycho-oncology consultation. Moreover, in view of the tablet entry into the Italian market, the full and reduced dosages of capsules and tablets were compared. This practical guidance is intended to be a tool to support especially less-experienced physicians in the management of these complex patients, with the aim to help preventing the worsening of patients' conditions and the unnecessary interruption/reduction of olaparib dosage, which may jeopardize treatment efficacy.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Anemia/induzido quimicamente , Antineoplásicos/uso terapêutico , Proteína BRCA1/genética , Proteína BRCA2/genética , Fadiga/induzido quimicamente , Feminino , Humanos , Itália , Mutação , Náusea/induzido quimicamente , Náusea/terapia , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/genética , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Vômito/induzido quimicamente
15.
Gynecol Oncol ; 156(3): 561-567, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31982178

RESUMO

OBJECTIVE: To measure preferences of women with ovarian cancer regarding risks, side effects, costs and benefits afforded by maintenance therapy (MT) with a poly ADP ribose polymerase (PARP) inhibitor. METHODS: A discrete-choice experiment elicited preferences of women with ovarian cancer regarding 6 attributes (levels in parentheses) relevant to decisions for MT versus treatment break: (1) overall survival (OS; 36, 38, 42 months); (2) progression-free survival (PFS; 15, 17, 21 months); (3) nausea (none, mild, moderate); (4) fatigue (none, mild, moderate); (5) probability of death from myelodysplastic syndrome/acute myelogenous leukemia (MDS/AML; 0% to 10%); (6) monthly out-of-pocket cost ($0 to $1000). Participants chose between 2 variable MT scenarios and a static scenario representing treatment break, with multiple iterations. Random-parameters logit regression was applied to model choices as a function of attribute levels. RESULTS: 95 eligible participants completed the survey; mean age was 62, 48% had recurrence, and 17% were ever-PARP inhibitor users. Participants valued OS (average importance weight 24.5 out of 100) and monthly costs (24.6) most highly, followed by risk of death from MDS/AML (17.9), nausea (14.7), PFS (10.5) and fatigue (7.8). Participants would accept 5% risk of MDS/AML if treatment provided 2.2 months additional OS or 4.8 months PFS. Participants would require gains of 2.6 months PFS to accept mild treatment-related fatigue and 4.4 months to accept mild nausea. CONCLUSIONS: When considering MT, women with ovarian cancer are most motivated by gains in OS. Women expect at least 3-4 months of PFS benefit to bear mild side effects of treatment.


Assuntos
Neoplasias Ovarianas/tratamento farmacológico , Preferência do Paciente/psicologia , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Tomada de Decisões , Feminino , Humanos , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/economia , Recidiva Local de Neoplasia/psicologia , Neoplasias Ovarianas/economia , Neoplasias Ovarianas/psicologia , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/economia , Intervalo Livre de Progressão , Taxa de Sobrevida , Estados Unidos
16.
Int J Gynecol Cancer ; 30(1): 89-93, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31792084

RESUMO

OBJECTIVE: To describe discrepancies in calculated and measured glomerular filtration rate in patients using PARP (poly ADP ribose polymerase) inhibitors who had an elevation in serum creatinine levels. METHODS: Retrospective cohort, single center study. Patients included were those with ovarian or endometrial cancer taking olaparib, rucaparib or niraparib, and in in whom an increased serum creatinine was identified. The study cohort included those who also underwent technetium-99m radioisotope renography (glomerular filtration rate (GFR) scan). The main objective is to describe the discrepancies in calculated glomerular filtration rate using the Cockcroft-Gault method and measured glomerular filtration rate using a GFR scan. RESULTS: 211 patients were included in the study; 64 (30%) had on-treatment elevated serum creatinine, and 23 (36%) underwent a GFR scan. 32 GFR scans were performed (six patients had more than one scan). Using a clinical cut-off ≥50 mL/min as normal renal function, both calculated and estimated glomerular filtration rates were below normal in 6 of 32 GFR scans. In those patients undergoing a GFR scan, serum creatinine had risen a median 49% (IQR 20-66%, range 0-144%) above baseline. Discordance between a calculated low glomerular filtration rate and an estimated normal glomerular filtration rate occurred in 63% (range of glomerular filtration rate discrepancy: -46% to +237%). Despite increases in serum creatinine on therapy and a subsequent significant decline in the per patient calculated creatinine clearance (mean 65.6 mL/min vs 43.4 mL/min; p<0.0001), the estimated glomerular filtration rate from the renal scan was nearly identical to the patient's baseline (65.6 mL/min vs 66.1 mL/min; p=0.89). CONCLUSIONS: Serum creatinine elevation in patients taking PARP inhibitors may not be associated with a true decrease in glomerular filtration rate. A high index of suspicion should be maintained for alternative causes of elevated serum creatinine in patients treated with PARP inhibitors who lack other sources of renal injury.


Assuntos
Neoplasias do Endométrio/tratamento farmacológico , Taxa de Filtração Glomerular/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Idoso , Ensaios Clínicos Fase III como Assunto , Estudos de Coortes , Creatinina/sangue , Neoplasias do Endométrio/sangue , Feminino , Humanos , Indóis/administração & dosagem , Pessoa de Meia-Idade , Neoplasias Ovarianas/sangue , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Renografia por Radioisótopo , Estudos Retrospectivos
17.
J Natl Cancer Inst ; 112(2): 161-169, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31076742

RESUMO

BACKGROUND: Women with epithelial ovarian cancer (OC) have a higher chance to benefit from poly (ADP-ribose) polymerase inhibitor (PARPi) therapy if their tumor has a somatic or hereditary BRCA1/2 pathogenic variant. Current guidelines advise BRCA1/2 genetic predisposition testing for all OC patients, though this does not detect somatic variants. We assessed the feasibility of a workflow for universal tumor DNA BRCA1/2 testing of all newly diagnosed OC patients as a prescreen for PARPi treatment and cancer predisposition testing. METHODS: Formalin-fixed paraffin-embedded tissue was obtained from OC patients in seven hospitals immediately after diagnosis or primary surgery. DNA was extracted, and universal tumor BRCA1/2 testing was then performed in a single site. Diagnostic yield, uptake, referral rates for genetic predisposition testing, and experiences of patients and gynecologists were evaluated. RESULTS: Tumor BRCA1/2 testing was performed for 315 (77.6%) of the 406 eligible OC samples, of which 305 (96.8%) were successful. In 51 of these patients, pathogenic variants were detected (16.7%). Most patients (88.2%) went on to have a genetic predisposition test. BRCA1/2 pathogenic variants were shown to be hereditary in 56.8% and somatic in 43.2% of patients. Participating gynecologists and patients were overwhelmingly positive about the workflow. CONCLUSIONS: Universal tumor BRCA1/2 testing in all newly diagnosed OC patients is feasible, effective, and appreciated by patients and gynecologists. Because many variants cannot be detected in DNA from blood, testing tumor DNA as the first step can double the identification rate of patients who stand to benefit most from PARP inhibitors.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/etiologia , Idoso , Gerenciamento Clínico , Feminino , Aconselhamento Genético , Predisposição Genética para Doença , Testes Genéticos , Humanos , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
18.
J Clin Oncol ; 38(5): 388-394, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-31461380

RESUMO

PURPOSE: Talazoparib has demonstrated efficacy in patients with BRCA-positive metastatic breast cancer. This study evaluated the pathologic response of talazoparib alone for 6 months in patients with a known germline BRCA pathogenic variant (gBRCA-positive) and operable breast cancer. METHODS: Eligibility included 1 cm or larger invasive tumor and gBRCA-positive disease. Human epidermal growth factor receptor 2-positive tumors were excluded. Twenty patients underwent a pretreatment biopsy, 6 months of once per day oral talazoparib (1 mg), followed by definitive surgery. Patients received adjuvant therapy at physician's discretion. The primary end point was residual cancer burden (RCB). With 20 patients, the RCB-0 plus RCB-I response rate can be estimated with a 95% CI with half width less than 20%. RESULTS: Twenty patients were enrolled from August 2016 to September 2017. Median age was 38 years (range, 23 to 58 years); 16 patients were gBRCA1 positive and 4 patients were gBRCA2 positive. Fifteen patients had triple-negative breast cancer (estrogen receptor/progesterone receptor < 10%), and five had hormone receptor-positive disease. Five patients had clinical stage I disease, 12 had stage II, and three had stage III, including one patient with inflammatory breast carcinoma and one with metaplastic chondrosarcomatous carcinoma. One patient chose to receive chemotherapy before surgery and was not included in RCB analyses. RCB-0 (pathologic complete response) rate was 53% and RCB-0/I was 63%. Eight patients (40%) had grade 3 anemia and required a transfusion, three patients had grade 3 neutropenia, and 1 patient had grade 4 thrombocytopenia. Common grade 1 or 2 toxicities were nausea, fatigue, neutropenia, alopecia, dizziness, and dyspnea. Toxicities were managed by dose reduction and transfusions. Nine patients required dose reduction. CONCLUSION: Neoadjuvant single-agent oral talazoparib once per day for 6 months without chemotherapy produced substantial RCB-0 rate with manageable toxicity. The substantive pathologic response to single-agent talazoparib supports the larger, ongoing neoadjuvant trial (ClinicalTrials.gov identifier: NCT03499353).


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Ftalazinas/administração & dosagem , Administração Oral , Adulto , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Feminino , Mutação em Linhagem Germinativa , Humanos , Adesão à Medicação , Pessoa de Meia-Idade , Terapia Neoadjuvante , Ftalazinas/efeitos adversos , Projetos Piloto , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética
19.
N Engl J Med ; 381(25): 2416-2428, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31851799

RESUMO

BACKGROUND: Olaparib has shown significant clinical benefit as maintenance therapy in women with newly diagnosed advanced ovarian cancer with a BRCA mutation. The effect of combining maintenance olaparib and bevacizumab in patients regardless of BRCA mutation status is unknown. METHODS: We conducted a randomized, double-blind, international phase 3 trial. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were having a response after first-line platinum-taxane chemotherapy plus bevacizumab. Patients were eligible regardless of surgical outcome or BRCA mutation status. Patients were randomly assigned in a 2:1 ratio to receive olaparib tablets (300 mg twice daily) or placebo for up to 24 months; all the patients received bevacizumab at a dose of 15 mg per kilogram of body weight every 3 weeks for up to 15 months in total. The primary end point was the time from randomization until investigator-assessed disease progression or death. RESULTS: Of the 806 patients who underwent randomization, 537 were assigned to receive olaparib and 269 to receive placebo. After a median follow-up of 22.9 months, the median progression-free survival was 22.1 months with olaparib plus bevacizumab and 16.6 months with placebo plus bevacizumab (hazard ratio for disease progression or death, 0.59; 95% confidence interval [CI], 0.49 to 0.72; P<0.001). The hazard ratio (olaparib group vs. placebo group) for disease progression or death was 0.33 (95% CI, 0.25 to 0.45) in patients with tumors positive for homologous-recombination deficiency (HRD), including tumors that had BRCA mutations (median progression-free survival, 37.2 vs. 17.7 months), and 0.43 (95% CI, 0.28 to 0.66) in patients with HRD-positive tumors that did not have BRCA mutations (median progression-free survival, 28.1 vs. 16.6 months). Adverse events were consistent with the established safety profiles of olaparib and bevacizumab. CONCLUSIONS: In patients with advanced ovarian cancer receiving first-line standard therapy including bevacizumab, the addition of maintenance olaparib provided a significant progression-free survival benefit, which was substantial in patients with HRD-positive tumors, including those without a BRCA mutation. (Funded by ARCAGY Research and others; PAOLA-1 ClinicalTrials.gov number, NCT02477644.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Terapia Combinada , Método Duplo-Cego , Feminino , Humanos , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/cirurgia , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de Progressão , Qualidade de Vida
20.
Gac Med Mex ; 155(6): 585-589, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31787769

RESUMO

Introduction: More than the twenty percent of ovarian cancers are hereditary, and most have BRCA mutations. The 30% of Mexican patients with the BRCA1 mutation have the BRCA1 gene exon 9-12del deletion founder mutation (BRCA1 ex9-12del). BRCA-mutated tumors are more sensitive to PARP inhibitors such as olaparib. Objective: To show the clinical experience on the use of olaparib at Instituto Nacional de Cancerología in Mexico. Method: Ovarian cancer patients treated with olaparib from November 2016 to December 2018 were studied, and their characteristics, clinical response, progression-free survival (PFS) and toxicities were described. Results: Nineteen patients were assessed, with BRCA1 mutation being found in 78.9%, out of which 21.1% were carriers of the ex9-12del founder mutation. The median of PFS was 12 months; for patients treated on second and third line it was > 15 months, and for those treated with a fourth and subsequent line it was 8.3 months. Patients with the founder mutation had better results. Toxicities were like those reported in previous studies. Conclusions: Olaparib offers greater PFS benefit as maintenance therapy after a first and second relapse. Patients with founder mutation have had sustained PFS.


Assuntos
Proteína BRCA1/genética , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Adulto , Idoso , Feminino , Humanos , México , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de Progressão
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