Circulating Tumor Cell Biomarker Panel As an Individual-Level Surrogate for Survival in Metastatic Castration-Resistant Prostate Cancer
Howard I. ScherGlenn HellerArturo MolinaGerhardt AttardDaniel C. DanilaXiaoyu JiaWeimin PengShahneen SandhuDavid OlmosRuth RiisnaesRobert G. McCormackTomasz BurzykowskiThian KheohMartin FleisherMarc BuyseJohann S. de Bono
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Abstract:
Trials in castration-resistant prostate cancer (CRPC) need new clinical end points that are valid surrogates for survival. We evaluated circulating tumor cell (CTC) enumeration as a surrogate outcome measure.Examining CTCs alone and in combination with other biomarkers as a surrogate for overall survival was a secondary objective of COU-AA-301, a multinational, randomized, double-blind phase III trial of abiraterone acetate plus prednisone versus prednisone alone in patients with metastatic CRPC previously treated with docetaxel. The biomarkers were measured at baseline and 4, 8, and 12 weeks, with 12 weeks being the primary measure of interest. The Prentice criteria were applied to test candidate biomarkers as surrogates for overall survival at the individual-patient level.A biomarker panel using CTC count and lactate dehydrogenase (LDH) level was shown to satisfy the four Prentice criteria for individual-level surrogacy. Twelve-week surrogate biomarker data were available for 711 patients. The abiraterone acetate plus prednisone and prednisone-alone groups demonstrated a significant survival difference (P = .034); surrogate distribution at 12 weeks differed by treatment (P < .001); the discriminatory power of the surrogate to predict mortality was high (weighted c-index, 0.81); and adding the surrogate to the model eliminated the treatment effect on survival. Overall, 2-year survival of patients with CTCs < 5 (low risk) versus patients with CTCs ≥ 5 cells/7.5 mL of blood and LDH > 250 U/L (high risk) at 12 weeks was 46% and 2%, respectively.A biomarker panel containing CTC number and LDH level was shown to be a surrogate for survival at the individual-patient level in this trial of abiraterone acetate plus prednisone versus prednisone alone for patients with metastatic CRPC. Additional trials are ongoing to validate the findings.Keywords:
Abiraterone acetate
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Circulating tumor cell
Introduction. In recent years, due to the progressive increase in the prevalence of castration-resistant prostate cancer (CRPC), the question of the sequence of prescription drugs is becoming more acute. Objective is to compare the effectiveness of various regimens of treatment of CRPC with the use of abirateron acetate and docetaxel. Materials and methods. The analysis included 83 patients with CRPC, which were divided into 2 groups depending on the sequence of appointment of abiraterone acetate and docetaxel. Results. Differences in the level of 2-year survival were statistically insignificant (73,2 % in the 1st group, 69 % in the 2nd group), and 3-year survival significantly differed: in the 1st group – 29,3 %, in the 2nd group – 16,7 % (p <0.05). Due to the short duration of the analysis, 5-year survival was not evaluated. The average value of overall survival in the appointment of the first docetaxel, then abiraterone acetate was 32 months, with the reverse regimen (abiraterone acetate, then docetaxel) – 27 months (p = 0.01). Conclusion . The scheme with the appointment of the first docetaxel, then abiraterone acetate is more effective from the point of view of affect on overall and 3-year survival in patients with CRPC.
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No AccessJournal of UrologyAdult Urology1 May 2013Re: Effect of Abiraterone Acetate and Prednisone Compared with Placebo and Prednisone on Pain Control and Skeletal-Related Events in Patients with Metastatic Castration-Resistant Prostate Cancer: Exploratory Analysis of Data from the COU-AA-301 Randomised Trial Samir S. TanejaM.D. Samir S. TanejaSamir S. Taneja More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.01.076AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Re: Effect of Abiraterone Acetate and Prednisone Compared with Placebo and Prednisone on Pain Control and Skeletal-Related Events in Patients with Metastatic Castration-Resistant Prostate Cancer: Exploratory Analysis of Data from the COU-AA-301 Randomised Trial." The Journal of Urology, 189(5), p. 1715 © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 5May 2013Page: 1715 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Samir S. Taneja More articles by this author Expand All Advertisement PDF downloadLoading ...
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To evaluate the efficacy and safety of abiraterone acetate (AA) plus prednisone compared with prednisone alone in Asian patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC), and to identify predictive factors.We reviewed the medical records of 60 patients with chemotherapy-naive mCRPC at Renji Hospital who were treated with AA plus prednisone (n = 43) or prednisone alone (n = 17). All patients were assessed for prostate-specific antigen (PSA) response, PSA progression-free survival (PSA PFS), radiographic progression-free survival (rPFS), and overall survival (OS). The ability of several parameters to predict PSA PFS, rPFS, and OS was studied.The median follow-up time was 14.0 months (range 7.0-18.5 months), at which time 19 death events had been reported: 11 in the AA + prednisone group and 8 in the prednisone group. The AA + prednisone group had significantly longer median PSA PFS (10.3 vs 3.0 months, P < 0.001), rPFS (13.9 vs 3.9 months, P < 0.001), and OS (23.3 vs 17.5 months, P = 0.016) than the prednisone-alone group. The most frequently reported grade 3 or 4 adverse event in both the AA + prednisone and prednisone-alone groups was elevated alanine aminotransferase level in 5 of 43 patients (11.6%) and 2 of 17 patients (11.8%), respectively. No adverse events led to discontinuation of therapy. In multivariate analysis, time from androgen deprivation therapy (ADT) to castration resistance of ≤18 months was a determinant of shorter OS (P = 0.007).These results support the favourable safety and efficacy profile of AA for the treatment of Asian patients with chemotherapy-naive mCRPC. Longer duration of ADT response was significantly associated with longer survival.
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62 歳，男性。4 型胃癌に対し胃全摘術を施行した。T 3， N 1， H 0， P 0， M 0， CYX であり，組織学的にはpoorly differentiated adenocarcinoma， ss， INF γ，ly2， v 2， n 2 であった。術後16 日目からTS-1 100mg/day を4 週投与2 週休薬を1 クールとして内服を開始，2 クールの投与を行った。投与終了ごろより腹部膨満感が出現し，CT を施行したところ著明な腹水の貯留を認めた。CEA は13.5ng/ml と上昇を示し，腹膜再発と診断した。外来にてdocetaxel40mg/body3 週投与1 週休薬を1 クールとして化学療法を開始した。CEA は6 クール目開始時には正常化した。CT でも腹水は消失しており，他の転移も認めなかったためCR と判定した。術後2 年，腹膜再発後1 年8 か月，10 クールのdocetaxel 投与終了後1 年経過した現在，無治療で観察中であるが再燃の徴候を認めていない。docetaxel の休薬や減量は不要であった。docetaxel のweekly 投与は安全に外来で施行可能なレジメンであり，胃癌領域でもその有効性が報告されている。本症例では胃癌に対して奏効率の高いTS-1 を投与中に発症した腹膜再発症例に対してdocetaxel が著効を示した。TS-1 無効例に対する治療についての検討は少ないが，FU 系の薬剤とは作用機序が異なることもあり，docetaxel のweekly 投与は有用な治療法となり得ると思われた。
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e20595 Background: Docetaxel is currently approved in non-small cell lung Cancer (NSCLC) after a failure of first line chemotherapy. However, docetaxel has an unfavorable toxicity profile that limits its use. A docetaxel-containing regimen with an improved safety profile would therefore be attractive. Plinabulin, a first-in-class small molecule vascular disruptive agent with potent immuno-oncology effects, is being developed in combination with docetaxel to address this need. Methods: We conducted a Phase 2 study comparing the safety and efficacy of the plinabulin /docetaxel combination (n=90) with docetaxel alone (n=73) in patients with NSCLC entering 2nd or 3rd line therapy. Plinabulin was given intravenously at 20 mg/m2 (n= 40) or 30 mg/m2 (n=50) and docetaxel at 75 mg/m2(n=73). Results: Efficacy results of this study were presented at ASCO 2014. Baseline characteristics for age, gender, ECOG performance score, histology and disease status were comparable between groups. The plinabulin/docetaxel combination improved overall survival, in a subset of patients with large tumors (> 3 cm; HR=0.758, p =0.36), and also had duration of response benefit over docetaxel alone (12.7 vs 1.5 months; P<0.05). We are reporting on the safety profile of plinabulin/ docetaxel combination. Conclusions: In this Phase 2 study, the plinabulin/docetaxel combination mitigated some of the docetaxel toxicities. Most importantly it improved docetaxel dose intensity. The neutropenia benefit was likely due to plinabulin-induced release of cytokines such as IL-1 and IL-6 (data obtained in in-vitro plinabulin studies), which are known to increase neutrophil count. In addition, preliminary results indicated a potential efficacy benefit of the plinabulin/docetaxel combination over docetaxel alone. A global Phase 3 trial with the plinabulin/docetaxel combination vs docetaxel alone is currently underway in the US, China, Australia and New Zealand. Clinical trial information: NCT00630110.Adverse events. Plinabulin/Docetaxel Docetaxel Grade 3/4 Neutropenia * 7 % 25 % Use of G-CSF * 14 % 29 % Sepsis 0 % 3.6 % Severe infections 0 % 3.6 % Asthenia * 13 % 28 % Docetaxel dose reduction due to toxicity * 6 % 20 % *p<0.01; Plinabulin/docetaxel combination vs docetaxel alone.
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