crpc雄激素通路治疗进展120.26.58.186 › 2018-11-23 ›...
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The Effect of Castration, of Estrogen, and of Androgen Injection on Serun Phosphatase in Metastatic Carcinoma of the Prostate
Huggins C, Hodges CV. Cancer Res. 1941;1:293-297.60
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Time (Days)
Stilbestrol, 1 mg daily
Acid Phosphatase
Alkaline Phosphatase
前列腺癌雄激素去除治疗(ADT)的历史
CRPC的定义
2016 EAU1
• 血清睾酮达去势水平*• 且以下条件满足一项即可:
− 生化进展:相隔一周, 连续3次PSA上升, 较最低值升高50%以上,且 PSA >2 ng/ml− 影像学进展:骨扫描发现≥ 2个骨病灶或RECIST(实体瘤疗效评价)评估软组织病灶增大
注:仅仅症状的进展不足以诊断CRPC
2015 AUA2
• 血清睾酮达去势水平*• PSA 升高幅度超过最低值 25%,升高值大于2ng/mL, ≥3周进行二次确认
1.EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Eur Urol. 2016 Aug 31. pii S0302-2838(16)30469-9.2. Castration-Resistant Prostate Cancer: AUA Guideline Amendment 2015. J Urol. 2016 May;195(5)1444-52.3. 2014年中国前列腺癌诊断治疗指南.
* 睾酮水平 <50ng/dL 或 <1.7nmol/L
2014 CUA3
• 血清睾酮达去势水平*• 相隔一周, 连续3次PSA上升, 较最低值升高50%以上
下丘脑
垂体
肾上腺
睾丸 雄激素(雄烯二酮、睾酮)
备选配体雄激素应答细胞
突变体
微管
联合因子
雄激素应答基因
转录激活(如,TMPRSS2 : ERG、PSA)
雄激素信号轴
Attard G et al. Clin Cancer Res 2011;17:1649-1657
去势治疗(ADT)
Dharia et al. Biol Report 2004; 71:83-88
睾丸、肾上腺以及产生雄激素的前列腺肿瘤组织均可表达
CYP17,CPY-17是雄激素产生的关键酶之一
阿比特龙作用机制
阿帕鲁胺作用机制
directly binds to the LBD of AR with high affinity, inhibiting its nuclear import and DNA binding capacity. 1) greater antitumor activity at a lower dose
and exposure than MDV3100; 2) steady-state levels of ARN-509 are 2- to 4-
fold lower than MDV3100 at equivalent doses, whereas intratumoral levels are equivalent, indicative of a higher tumor/plasma ratio for ARN-509;
3) brain levels of ARN-509 are 4-fold lower than MDV3100, suggesting a reduced risk of seizure activity.
Cancer Res. 2012 Mar 15;72(6):1494-503.
FOR INTERNAL PURPOSES ONLY
新型抗雄药物的优势:Enzalutamide vs Bicalutamide
• Shore ND et al. Lancet Oncol. 2016;17:153-63.
• PROSPER:III期随机、对照、双盲研究(NCT02003924)
• 目的:评估恩杂鲁胺(160mg)治疗M0 CRPC的疗效
• 入组:M0 CRPC and PSA-DT≤10 mo and PSA≥2ng/ml (N=1401,2:1分为ENZA+ADT/PBO+ADT)
• 主要终点:MFS
• 次要终点:OS
恩杂鲁胺在M0CRPC患者中的疗效——PROSPER研究
• 在M0 CRPC、PSA快速倍增(中位3.7个月)的患者中,恩杂鲁胺降低了71%的进展为M1 CRPC的相对风险--中位PFS恩杂鲁胺组36.6个月vs安慰剂组14.7个月(HR, 0.29; P<0.0001)
• 治疗耐受性良好;总体上副作用与之前的CRPC临床试验结果基本一致
• 恩杂鲁胺同样显著延长了次要终点(至PSA进展时间、至首次使用新抗肿瘤治疗时间)
• 中位OS在首次中期分析时两组均未达到,恩杂鲁胺组并未获得OS获益
恩杂鲁胺在M0CRPC患者中的疗效——PROSPER研究
EAU 2018,abstruct 604
SPARTAN, a Phase 3 Double-Blind, Randomized Study of Apalutamide vs Placebo in Patients With Nonmetastatic Castration-Resistant Prostate Cancer
Slide 5
Presented By Eric Small at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
Presented By Eric Small at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
CRPC新型内分泌治疗:治疗前提可获更好疗效?
nmCRPCEnzalutamide
PFS 36.6m vs 14.7mOS 3y约 80% vs 70%
ApalutamidePFS 40.5m vs 16.2m
OS 3y 约80%
AbirateronePFS 16.5m vs 8.2mOS 35.3m vs 30.1m
3y 约 40+%
EnzalutamidePFS NR m vs 14.8mOS 32.4m vs 30.2m
3y 约 40+%
mCRPC
?
CRPC 新型内分泌治疗:应用更加广泛
mCRPC 化疗后 未化疗
Abiraterone COU-AA-301(2011) COU-AA-302(2012)
Enzalutamide AFFIRM(2012) PREVAIL(2013)
CRPC(未化疗) M1 M0 M0
Enzalutamide TERRAIN / STRIVE(Vs. Bicalutamide)
STRIVE(Vs. Bicalutamide)
PROSPER(2018)
Apalutamide SPARTAN(2018)