RESUMO
OBJECTIVE: To investigate the association of radiographic progression defined by Prostate Cancer Working Group (PCWG)-2 guidelines and overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Two trials that used PCWG-2 guidelines to define progression were analysed: a randomized phase II trial (n = 221) comparing first-line docetaxel-prednisone plus AT-101 or placebo, and a phase III trial (n = 873) comparing prednisone plus sunitinib or placebo after docetaxel-based chemotherapy. Cox proportional hazards regression models were used to estimate the association of radiographic progression with OS. Landmark analyses compared progressing patients with those who had not progressed. Sub-analyses compared patients removed from trial for progression vs other reasons. RESULTS: An increased risk of death was seen for radiographic progression at landmark times from 6 to 12 months with docetaxel-based therapy (hazard ratio [HR] >1.7 at all time-points). An increased risk of death was also seen with post-docetaxel prednisone alone or with sunitinib for progression at landmark times from 2 to 8 months (HR >2.7 at all time-points). Kendall's τ was 0.50 (P < 0.001) in the setting of docetaxel-based therapy and 0.34 (P < 0.001) in the post-docetaxel setting for association between radiographic progression and death amongst patients with both events. Removal from study due to radiographic progression was associated with a significantly lower OS compared with removal for other reasons in both trials. Limitations of a retrospective analysis apply and there was no central radiology review. CONCLUSIONS: Radiographic progression by PCWG-2 criteria was significantly associated with OS in patients with mCRPC receiving first-line docetaxel-based chemotherapy or post-docetaxel therapy. With external validation as a surrogate endpoint in trials showing survival benefits, the use of radiographic progression-free survival may expedite drug development in mCRPC, which has been hampered by the lack of intermediate endpoints.
Assuntos
Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Progressão da Doença , Intervalo Livre de Doença , Docetaxel , Descoberta de Drogas , Gossipol/administração & dosagem , Gossipol/análogos & derivados , Humanos , Indóis/administração & dosagem , Masculino , Prednisona/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/patologia , Pirróis/administração & dosagem , Radiografia , Estudos Retrospectivos , Sunitinibe , Taxa de Sobrevida , Taxoides/administração & dosagem , Fatores de TempoRESUMO
UNLABELLED: What's known on the subject? and What does the study add? Serum C-reactive protein (C-reactive protein) is emerging as a potential novel prognostic factor in metastatic castration-resistant prostate cancer (mCRPC). In the present study, a prospective trial was investigated retrospectively and a significant prognostic impact for C-reactive protein that was independent of multiple published prognostic models was identified in men receiving docetaxel-based chemotherapy for mCRPC. Prospective validation is warranted. OBJECTIVE: ⢠Given the recent emergence of C-reactive protein levels as a novel prognostic factor in men with metastatic castration-resistant prostate cancer (mCRPC), we sought to evaluate the independent prognostic ability of C-reactive protein in the context of published prognostic nomograms, risk grouping and disease state models in men receiving docetaxel-based chemotherapy for mCRPC. PATIENTS AND METHODS: ⢠A large randomized phase II trial (CS-205) of mCRPC patients who received docetaxel-prednisone + AT-101 (Bcl-2 inhibitor) or docetaxel-prednisone + placebo was analyzed retrospectively (n= 220). ⢠Overall survival (OS), progression-free survival (PFS) and measures of discriminatory ability were assessed in a hypothesis-generating analysis using Cox regression and concordance probabilities. ⢠Patients from both treatment groups were combined for this analysis because no significant differences in outcomes were observed. ⢠Because some factors used in nomograms were not collected or defined differently, risk was estimated based on slightly modified versions of nomograms. RESULTS: ⢠C-reactive protein was independently prognostic for OS and PFS (P ≤ 0.002) after adjusting for all modeled risk estimates and classifiers. ⢠C-reactive protein showed a concordance probability of 0.65 for both OS and PFS. ⢠A 10-factor modified prognostic model based on the TAX327 trial had the greatest observed discrimination ability for OS and PFS (concordance probability = 0.623 and 0.603, respectively) among the modified nomograms or classifiers. ⢠Adding the TAX327 model risk estimates to C-reactive protein did not substantially increase discrimination ability over C-reactive protein alone. CONCLUSIONS: ⢠Current prognostic classifications provide modest discrimination of outcomes in mCRPC receiving docetaxel-based chemotherapy, highlighting the need for improved risk-based models. ⢠Baseline C-reactive protein appears to be an useful, independent prognostic factor and prospective external validation is warranted.
Assuntos
Proteína C-Reativa/metabolismo , Orquiectomia , Neoplasias da Próstata/sangue , Taxoides/administração & dosagem , Antineoplásicos/administração & dosagem , Biomarcadores Tumorais/sangue , Intervalo Livre de Doença , Docetaxel , Relação Dose-Resposta a Droga , Humanos , Masculino , Prognóstico , Estudos Prospectivos , Neoplasias da Próstata/secundário , Neoplasias da Próstata/terapia , RadiossensibilizantesRESUMO
OBJECTIVES: Abiraterone acetate (AA) is a CYP17 inhibitor of androgen synthesis approved for use following docetaxel for metastatic castration-resistant prostate cancer (mCRPC); evaluation in the pre-docetaxel setting is ongoing. Given that the reported efficacy of AA is lower following docetaxel vs. pre-docetaxel, the potential exists for cross resistance given docetaxel's partly androgen receptor targeting activity. The efficacy of docetaxel following ketoconazole (KC), a weaker and nonspecific inhibitor of CYP17, may provide some insights into this potential interaction. We retrospectively evaluated the efficacy of every 3-week docetaxel with prednisone (DP) in mCRPC previously exposed to KC compared to KC-naive patients. MATERIALS AND METHODS: A randomized phase II trial of men with mCRPC treated with DP + AT-101 (bcl-2 inhibitor) vs. DP plus placebo was analyzed. Both arms were combined for analysis as no significant differences were seen. Overall survival (OS), progression-free survival (PFS), objective response (ORR), pain, and prostate-specific antigen (PSA) response rates were estimated with and without prior KC. Cox proportional hazards regression models were used to estimate the effect of covariates on OS. RESULTS: Of 220 evaluable men, 40 (18.2%) received prior KC. The median OS with DP-based therapy of KC-naive patients (18.3 months, 95% CI: 15.0, 24.5) and post-KC patients (17.0 months, 95% CI: 9.9, 20.4) was not statistically different (P = 0.20). After controlling for prognostic classifications, analyses demonstrated consistent trends for worsening of OS after KC, with (hazard ratios (HRs) 1.33-1.46. Similar unfavorable trends were observed for ORR, PSA declines, and PFS. CONCLUSIONS: In this hypothesis-generating analysis, patients treated with docetaxel-based chemotherapy following prior KC had numerically and consistently worse outcomes than patients not exposed to prior KC. Although the estimated differences did not attain statistical significance, evaluation of outcomes with docetaxel in particular, and all classes of novel and emerging agents following AA, is of clinical importance, given its more potent androgen synthesis inhibition compared with KC. Drug development should take into account the potential impact of previous therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Intervalo Livre de Doença , Docetaxel , Gossipol/administração & dosagem , Gossipol/análogos & derivados , Humanos , Cetoconazol/administração & dosagem , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Prednisona/administração & dosagem , Modelos de Riscos Proporcionais , Estudos Prospectivos , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos , Taxoides/administração & dosagemRESUMO
BACKGROUND: Docetaxel clearance appears increased in men who are castrated. Neutropenia in cycle 1 may be a pharmacodynamic marker for docetaxel, which may enable tailored dosing in metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: The association of cycle 1 neutropenia with overall survival (OS) was examined post hoc in a randomized phase II trial of 221 men with mCRPC who received docetaxel-prednisone combined with placebo or AT-101 (bcl-2 inhibitor); weekly blood cell counts were performed during the first cycle. Patients from both arms were combined because no outcome and toxicity differences were observed. OS was calculated from randomization by the Kaplan-Meier method, and Cox proportional hazards regression models were used to estimate the association with OS. RESULTS: The difference in OS between men with day 8 ≥grade 3 neutropenia and those with ≤grade 2 neutropenia was significant after adjusting for trial stratification factors, pain, and performance status (hazard ratio [HR] 0.64; 2P = .048). Results were similar for logarithmic neutrophil counts adjusted for the risk group based on anemia, visceral metastasis, progression by bone scan and pain (HR 1.18; 2P = .07) for stratification factors (HR 1.20; 2P = .052) or both (HR, 1.20; 2P = .046). Men with ≥grade 3 neutropenia and ≥30% prostate-specific antigen level decline by day 90 had improved OS compared with men exhibiting neither (HR 0.51; 2P = .014). CONCLUSIONS: For patients with mCRPC who received docetaxel, ≥grade 3 neutropenia on day 8 was prognostic for improved OS, which suggests its utility as a pharmacodynamic marker, in this hypothesis-generating analysis. Exploration of dose escalation of docetaxel to attain ≥grade 3 neutropenia on day 8 may be warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neutropenia/induzido quimicamente , Neoplasias da Próstata/tratamento farmacológico , Taxoides/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Intervalo Livre de Doença , Docetaxel , Gossipol/administração & dosagem , Gossipol/análogos & derivados , Humanos , Estimativa de Kaplan-Meier , Masculino , Metástase Neoplásica , Prednisona/administração & dosagem , Prognóstico , Antígeno Prostático Específico/sangue , Estudos Retrospectivos , Análise de SobrevidaRESUMO
BACKGROUND: The optimal number of 3-wk docetaxel plus prednisone (DP) cycles for metastatic castration-resistant prostate cancer (mCRPC) is unclear. OBJECTIVE: A retrospective analysis of two clinical trials was performed to evaluate the association of the number of cycles with overall survival (OS). DESIGN, SETTING, AND PARTICIPANTS: An exploratory analysis compared outcomes of 332 men who received DP in the TAX-327 trial, which stipulated up to 10 cycles, and 220 men who received DP in CS-205, a randomized phase 2 trial comparing DP plus AT-101 (bcl-2 inhibitor) versus DP plus placebo, which allowed up to 17 cycles. MEASUREMENTS: Patients who completed 10 cycles of DP without progression in both trials were included. Men in both arms of CS-205 were combined for analysis, as no significant differences in outcomes were observed. OS was estimated from the date of cycle 10 docetaxel infusion. RESULTS AND LIMITATIONS: The number of men receiving 10 cycles was similar (p=0.26) in the two trials (166 [50.0%] in TAX-327 vs 99 [45.0%] in CS-205; the latter group received a median of five additional cycles). Six- and 12-mo estimated survival after cycle 10 was 92.2% (95% confidence interval [CI], 86.9-95.4%) and 74.6% (CI, 67.2-80.5%) in TAX-327, compared with 92.8% (CI, 85.5-96.5) and 63.4% (CI, 51.8-72.9%) in CS-205. Subanalyses suggested that <10 cycles may have a negative impact and prostate-specific antigen (PSA) declines at cycle 10 may carry a favorable impact. The significance of continued PSA declines up to 17 cycles is unclear. Limitations of a retrospective analysis apply. CONCLUSIONS: A survival benefit was not detected with >10 cycles of DP in men with mCRPC in this retrospective hypothesis-generating analysis.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Gossipol/análogos & derivados , Prednisona/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/mortalidade , Taxoides/administração & dosagem , Idoso , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/secundário , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Docetaxel , Gossipol/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: AT-101 is an inhibitor of Bcl-2 family proteins including Bcl-2, Bcl-xL, Mcl-1, and Bcl-w. In vivo and in vitro studies have exhibited broad activity of AT-101, including synergy with docetaxel in non-small cell lung cancer tumor models. METHODS: We conducted a prospective, randomized (1:1), double-blind, placebo-controlled phase 2 study. Eligible patients must have received one prior chemotherapeutic regimen for advanced or metastatic non-small cell lung cancer and may also have received therapy with an epidermal growth factor receptor inhibitor. Patients received AT-101 (40 mg b.i.d. × 3 days) or placebo in combination with docetaxel (75 mg/m on day 1) every 21 days. The primary endpoint was progression-free survival (PFS) as determined by independent review; other endpoints include overall survival and PFS by investigator determination. Approximately 102 patients were planned to provide 70 events (80% power, hazard ratio [HR] of 0.6, one-sided alpha of 0.1). RESULTS: : One hundred six patients were assigned to treatment and 105 patients received at least one dose of AT-101 or placebo. Baseline factors were balanced between treatment groups: median age 59 years; 77% men, and 79% current or former smokers. Ninety-three percent of patients had distant metastatic disease at randomization and 56% squamous histology. The most frequently reported adverse events were fatigue (18%), anemia (18%), and dyspnea (18%). No statistically significant differences in serious adverse events were observed between AT-101 and placebo; grade 1/2 headaches appeared more frequently with AT-101 (9% versus 0%) and neutropenia was reported more frequently in the docetaxel plus placebo arm compared with docetaxel plus AT-101 (17% versus 8%). Unlike trials with continuous daily dosing of AT-101, no cases of small bowel obstruction were reported. The response rate and median PFS were not different between the arms by independent review, PFS 7.5 weeks for docetaxel plus AT-101 and 7.1 weeks for docetaxel plus placebo arms (HR, 1.04; p = 0.57). The median overall survival was 7.8 months for docetaxel plus AT-101 versus 5.9 months for docetaxel plus placebo (HR, 0.82; p = 0.21). CONCLUSIONS: The primary endpoint of improved PFS for AT-101 plus docetaxel was not met. AT-101 plus docetaxel was well tolerated with an adverse event profile indistinguishable from the base docetaxel regimen. AT-101 is the first oral, pan Bcl-2 family inhibitor to exhibit a possible survival benefit in a randomized study.