Antonarakis Emmanuel S, Tagawa Scott T, Galletti Giuseppe, Worroll Daniel, Ballman Karla, Vanhuyse Marie, Sonpavde Guru, North Scott, Albany Costantine, Tsao Che-Kai, Stewart John, Zaher Atef, Szatrowski Ted, Zhou Wei, Gjyrezi Ada, Tasaki Shinsuke, Portella Luigi, Bai Yang, Lannin Timothy B, Suri Shalu, Gruber Conor N, Pratt Erica D, Kirby Brian J, Eisenberger Mario A, Nanus David M, Saad Fred, Giannakakou Paraskevi
Emmanuel S. Antonarakis and Mario A. Eisenberger, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Scott T. Tagawa, Giuseppe Galletti, Daniel Worroll, Karla Ballman, Ada Gjyrezi, Shinsuke Tasaki, Luigi Portella, Yang Bai, Brian J. Kirby, David M. Nanus, and Paraskevi Giannakakou, Weill Cornell Medicine/Meyer Cancer Center; Che-Kai Tsao, Mount Sinai Medical Center, New York; Timothy B. Lannin, Shalu Suri, Conor N. Gruber, Erica D. Pratt, and Brian J. Kirby, Cornell University, Ithaca, NY; Marie Vanhuyse, Medical Oncology, Montréal General Hospital; Fred Saad, University of Montreal Hospital Center, Montreal; John Stewart, Atef Zaher, and Wei Zhou, Sanofi, Laval, Quebec, Canada; Guru Sonpavde, University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL; Scott North, University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada; Costantine Albany, Indiana University School of Medicine, Indianapolis, IN; and Ted Szatrowski, Sanofi, Bridgewater, NJ.
J Clin Oncol. 2017 Oct 1;35(28):3181-3188. doi: 10.1200/JCO.2017.72.4138. Epub 2017 Jun 20.
Purpose The TAXYNERGY trial ( ClinicalTrials.gov identifier: NCT01718353) evaluated clinical benefit from early taxane switch and circulating tumor cell (CTC) biomarkers to interrogate mechanisms of sensitivity or resistance to taxanes in men with chemotherapy-naïve, metastatic, castration-resistant prostate cancer. Patients and Methods Patients were randomly assigned 2:1 to docetaxel or cabazitaxel. Men who did not achieve ≥ 30% prostate-specific antigen (PSA) decline by cycle 4 (C4) switched taxane. The primary clinical endpoint was confirmed ≥ 50% PSA decline versus historical control (TAX327). The primary biomarker endpoint was analysis of post-treatment CTCs to confirm the hypothesis that clinical response was associated with taxane drug-target engagement, evidenced by decreased percent androgen receptor nuclear localization (%ARNL) and increased microtubule bundling. Results Sixty-three patients were randomly assigned to docetaxel (n = 41) or cabazitaxel (n = 22); 44.4% received prior potent androgen receptor-targeted therapy. Overall, 35 patients (55.6%) had confirmed ≥ 50% PSA responses, exceeding the historical control rate of 45.4% (TAX327). Of 61 treated patients, 33 (54.1%) had ≥ 30% PSA declines by C4 and did not switch taxane, 15 patients (24.6%) who did not achieve ≥ 30% PSA declines by C4 switched taxane, and 13 patients (21.3%) discontinued therapy before or at C4. Of patients switching taxane, 46.7% subsequently achieved ≥ 50% PSA decrease. In 26 CTC-evaluable patients, taxane-induced decrease in %ARNL (cycle 1 day 1 v cycle 1 day 8) was associated with a higher rate of ≥ 50% PSA decrease at C4 ( P = .009). Median composite progression-free survival was 9.1 months (95% CI, 4.9 to 11.7 months); median overall survival was not reached at 14 months. Common grade 3 or 4 adverse events included fatigue (13.1%) and febrile neutropenia (11.5%). Conclusion The early taxane switch strategy was associated with improved PSA response rates versus TAX327. Taxane-induced shifts in %ARNL may serve as an early biomarker of clinical benefit in patients treated with taxanes.
目的 “TAXYNERGY试验”（ClinicalTrials.gov标识符：NCT01718353）评估了对于未经化疗、转移性、去势抵抗性前列腺癌男性患者，早期紫杉烷转换及循环肿瘤细胞（CTC）生物标志物在探究对紫杉烷敏感性或耐药性机制方面的临床获益情况。
患者与方法 患者按2:1随机分配至多西他赛或卡巴他赛组。在第4周期（C4）时前列腺特异性抗原（PSA）下降未达到≥30%的男性患者更换紫杉烷。主要临床终点是确认PSA下降≥50%并与历史对照（TAX327）进行比较。主要生物标志物终点是分析治疗后的CTC，以证实临床反应与紫杉烷药物靶点结合相关这一假设，证据是雄激素受体核定位百分比（%ARNL）降低和微管束增加。
结果 63例患者被随机分配至多西他赛组（n = 41）或卡巴他赛组（n = 22）；44.4%的患者接受过先前有效的雄激素受体靶向治疗。总体而言，35例患者（55.6%）确认PSA反应≥50%，超过了45.4%的历史对照率（TAX327）。在61例接受治疗的患者中，33例（54.1%）在C4时PSA下降≥30%且未更换紫杉烷，15例（24.6%）在C4时PSA下降未达到≥30%的患者更换了紫杉烷，13例（21.3%）在C4之前或C4时停止治疗。在更换紫杉烷的患者中，46.7%随后PSA下降≥50%。在26例可进行CTC评估的患者中，紫杉烷诱导的%ARNL下降（第1周期第1天与第1周期第8天相比）与C4时PSA下降≥50%的更高发生率相关（P = .009）。中位无进展生存期为9.1个月（95%CI，4.9至11.7个月）；14个月时总生存期未达到中位值。常见的3级或4级不良事件包括疲劳（占13.1%）和发热性中性粒细胞减少（占11.5%）。
结论 与TAX327相比，早期紫杉烷转换策略与PSA反应率提高相关。紫杉烷诱导的%ARNL变化可能作为接受紫杉烷治疗患者临床获益的早期生物标志物。
