阿比特龙序贯恩扎卢胺治疗转移性去势抵抗性前列腺癌临床分析

龙星博; 杨振宇; 王骏; 赵迪威; 赵峻樑; 陈东; 周芳坚; 李永红

doi:10.13201/j.issn.1001-1420.2024.01.006

阿比特龙序贯恩扎卢胺治疗转移性去势抵抗性前列腺癌临床分析

- 中山大学肿瘤防治中心泌尿外科华南肿瘤学国家重点实验室肿瘤医学协同创新中心(广州，510060)

详细信息

通讯作者: 李永红，E-mail：liyongh@sysucc.org.cn

中图分类号: R735.25

收稿日期: 2023-11-18

刊出日期: 2024-01-06

Clinical analysis of sequential treatment using abiraterone and enzalutamide for metastatic castration-resistant prostate cancer

- Department of Urology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China

More Information

Corresponding author: LI Yonghong, E-mail: liyongh@sysucc.org.cn

Received Date: 18 November 2023

Publish Date: 06 January 2024

摘要

摘要: 目的阿比特龙序贯恩扎卢胺治疗是转移性去势抵抗性前列腺癌(metastatic castration-resistant prostate cancer，mCRPC)患者可选择的治疗方式之一，可使部分患者获益。然而，尚缺乏这种序贯治疗方案在中国mCRPC人群真实世界的数据。方法回顾性分析2018年1月—2023年4月于中山大学肿瘤防治中心采用阿比特龙序贯恩扎卢胺治疗的136例mCRPC患者的临床资料。根据转移性激素敏感性前列腺癌(metastatic hormone-sensitive prostate cancer，mHSPC)阶段治疗方案分为联合治疗组和阶梯治疗组。其中联合治疗组57例，患者在mHSPC阶段使用雄激素剥夺治疗(androgen deprivation therapy，ADT)联合阿比特龙+泼尼松治疗; 阶梯治疗组79例，患者在mHSPC阶段仅使用ADT治疗，进展为mCRPC再联合阿比特龙+泼尼松治疗。主要研究终点是恩扎卢胺治疗PSA最大下降比例超过50%(PSA50)的情况结果恩扎卢胺平均使用时间为(4.5±2.2)个月，18.38%的患者达到PSA50。多因素分析显示mHSPC阶段治疗方案(联合治疗组vs阶梯治疗组)(OR＝4.52，95%CI：1.27~16.14，P=0.02)、阿比特龙有效时间(OR＝1.11，95%CI：1.03~1.19，P=0.005)和阿比特龙治疗进展后到序贯恩扎卢胺的间隔时间(OR＝0.83，95%CI：0.72~0.95，P=0.007)是PSA50的独立预测因素。采用倾向性评分根据临床基线特征对联合治疗组和阶梯治疗组间的患者进行1∶1匹配，结果显示联合治疗组相对于阶梯治疗组患者有着更高的PSA50(31.58% vs 7.02%)。结论阿比特龙序贯恩扎卢胺可使部分mCRPC患者获得PSA反应。阿比特龙有效时间长，在mHSPC期使用ADT联合阿比特龙治疗，以及阿比特龙耐药后序贯恩扎卢胺时间间隔短的患者更可能在序贯治疗中出现PSA50。
- 转移性去势抵抗性前列腺癌 /
- 阿比特龙 /
- 恩扎卢胺
Abstract: Objective To analyze the real-world data on the sequential treatment regimen of abiraterone acetate followed by enzalutamide in Chinese patients with metastatic castration-resistant prostate cancer(mCRPC). Methods The retrospective analysis included 136 mCRPC patients treated with abiraterone acetate followed by enzalutamide from January 2018 to April 2023. The patients were divided into two groups based on the treatment strategy in the metastatic hormone-sensitive prostate cancer(mHSPC) stage: the "combination therapy" group and the "step-wise therapy" group. In the combined therapy group, 57 patients received androgen deprivation therapy(ADT) combined with abiraterone and prednisone during the mHSPC stage. In the step-wise therapy group, 79 patients were initially treated with ADT during the mHSPC stage, and subsequently progressed to mCRPC before receiving combined treatment with abiraterone plus prednisone. The primary endpoint was the proportion of patients with a PSA maximum decline of over 50%(PSA50) following enzalutamide treatment. Results The mean duration of enzalutamide use was(4.5±2.2) months, and 18.38% of patients achieved a PSA50 response. Multifactorial analysis revealed that the treatment strategy at the mHSPC stage(combined treatment vs. step-wise treatment)(OR＝4.52, 95%CI: 1.27-16.14, P=0.02), the effective duration of abiraterone(OR＝1.11, 95%CI: 1.03-1.19, P=0.005), and the time interval from frontline abiraterone treatment progression to sequential enzalutamide(OR＝0.83, 95%CI: 0.72-0.95, P=0.007) were independent predictive factors for PSA50. By using propensity score matching based on clinical baseline characteristics, patients in the combination therapy group and the step-wise therapy group were matched at a 1∶1 ratio. The results demonstrated that patients in the combination therapy group had a higher PSA50 response compared to those in the step-wise therapy group(31.58% vs 7.02%). Conclusion Sequential treatment using abiraterone acetate and enzalutamide can lead to PSA response in some mCRPC patients. Those with longer frontline abiraterone effective duration, a shorter time interval from frontline abiraterone treatment progression to sequential enzalutamide, and the use of ADT combined with abiraterone therapy strategy during the mHSPC period are more likely to experience PSA50 during sequential therapy.
- metastatic castration-resistant prostate cancer /
- abiraterone /
- enzalutamide

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表 1 队列总人群和不同分组患者临床基线特征、前线治疗过程和序贯恩扎卢胺前情况例(%)，X±S，M(P₂₅，P₇₅)

项目	总人群(136例)	无反应组(111例)	PSA50组(25例)	P值
临床基线特征
年龄/岁	72.19±9.02	72.20±8.88	72.16±9.81	0.98
GG				0.16
GG3	22(16.2)	15(13.5)	7(28.0)
GG4	41(30.1)	36(32.4)	5(20.0)
GG5	73(53.7)	60(54.1)	13(52.0)
诊断时PSA/(ng/mL)	155.75(66.00，353.43)	158(66.00，354.90)	143.00(64.32，459.85)	0.84
BMI/(kg/m²)^a)	23.27(23.27±3.86)	23.21±3.95	23.59±3.44	0.72
临床T分期				0.24
T2	7(5.1)	4(3.6)	3(12.0)
T3a	15(11.0)	14(12.6)	1(4.0)
T3b	58(42.6)	47(42.3)	11(44.0)
T4	56(41.2)	46(41.4)	10(40.0)
临床N分期				0.59
N0	48(35.3)	38(34.2)	10(40.0)
N1	88(64.7)	73(65.8)	15(60.0)
临床M分期				0.37
M0	29(21.3)	22(19.8)	7(28.0)
M1b(转移＜4个转移部位)	27(19.9)	22(19.8)	5(20.0)
M1b(≥4个转移部位且≥1处在椎体和骨盆之外)	69(50.7)	56(50.5)	13(52.0)
M1c	11(8.1)	11(9.9)	0(0)
前线治疗过程
mHSPC阶段治疗策略				＜0.01
阶梯治疗	79(58.1)	72(64.9)	7(28.0)
联合治疗	57(41.9)	39(35.1)	18(72.0)
阿比特龙治疗最低PSA/(ng/mL)	1.36(0.18，7.87)	1.61(0.30，9.18)	0.15(0.054，2.98)	＜0.01
阿比特龙治疗有效时间/月	9(5，14)	8(4，12)	15(12.5，22)	＜0.01
阿比特龙治疗PSA下降率/%	89.86(43.78，99.25)	85.83(30.65，98.56)	99.56(90.64，99.91)	＜0.01
阿比特龙治疗进展到使用恩扎卢胺间隔时间/月	7.00(3.00，13.00)	8.00(4.00，15.00)	4.00(3.00，7.50	＜0.01
阿比特龙治疗时是否进行激素转换				0.56
否	80(58.8)	64(57.7)	16(64.0)
是	56(41.2)	47(42.3)	9(36.0)
转移灶是否接受放疗				0.35
否	124(91.2)	100(90.1)	24(96.0)
是	12(8.8)	11(9.9)	1(4.0)
是否接受多西他赛化疗				0.98
否	114(83.8)	93(83.8)	21(84.0)
是	22(16.2)	18(16.2)	4(16.0)
是否对原发灶进行治疗				0.29
否	79(58.1)	65(58.6)	14(56.0)
前列腺癌根治术	33(24.3)	24(21.6)	9(36.0)
根治性放疗	18(13.2)	16(14.4)	2(8.0)
冷冻治疗	6(4.4)	6(5.4)	0(0)
序贯恩扎卢胺前情况
序贯恩扎卢胺前PSA /(ng/mL)	19.95(6.23，74.92)	20.00(6.34，72.60)	15.5(4.30，123.00)	0.60
序贯恩扎卢胺前PSA倍增时间/月	3.19±2.32	3.32±2.33	2.64±2.27	0.19
序贯恩扎卢胺前NSE/(ng/mL)^b)	13.58(11.07，16.55)	13.50(10.90，16.57)	14.77(12.44，16.75)	0.24
序贯恩扎卢胺前转移情况				0.37
M1b(＜4个转移部位)	29(21.3)	22(19.8)	7(28.0)
M1b(≥4个转移部位且≥1处在椎体和骨盆之外)	92(67.6)	75(67.6)	17(68.0)
M1c	15(11.0)	14(12.6)	1(4.0)
注：前列腺癌分级分组(grade group，GG)。^a)105例患者有BMI数据，其中无反应组89例，PSA50组16例; ^b)114例患者有序贯恩扎卢胺前NSE数据，其中无反应组96例，PSA50组18例。

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表 2 logistic单因素和多因素分析与PSA50相关临床因素

变量	单因素分析		多因素分析
变量	OR(95%CI)	P值	OR(95%CI)	P值
年龄	1.00(0.95~1.05)	0.99
诊断时PSA	1.00(0.99~1.00)	0.35
BMI^a)
≥25 kg/m² vs ＜25 kg/m²	1.15(0.39~3.38)	0.80
未知vs ＜25 kg/m²	1.64(0.57~4.70)	0.35
GG
GG4 vs GG3	0.30(0.08~1.09)	0.07
GG5 vs GG3	0.46(0.16~1.37)	0.16
临床T分期
T3b vs ≤T3a	0.88(0.24~3.22)	0.85
T4 vs ≤T3a	1.15(0.33~4.03)	0.83
临床N分期(N1 vs N0)	0.78(0.32~1.90)	0.59
临床M分期(高瘤负荷vs无转移和底瘤负荷)	0.71(0.30~1.70)	0.44
mHSPC阶段治疗策略(联合治疗vs阶梯治疗)	4.75(1.83~12.40)	＜0.01	4.52(1.27~16.14)	0.02
转移灶是否接受放疗(是vs否)	0.38(0.05~3.08)	0.36
是否接受化疗(是vs否)	0.98(0.30~3.21)	0.98
是否进行局灶治疗(是vs否)	1.23(0.51~1.99)	0.65
阿比特龙治疗有效时间(连续变量)	1.10(1.04~1.16)	＜0.01	1.11(1.03~1.19)	＜0.01
阿比特龙治疗PSA下降率(连续变量)	2.54(0.79~8.12)	0.12
阿比特龙治疗时是否进行激素转换(是vs否)	0.77(0.31~1.88)	0.56
阿比特龙治疗进展到序贯恩扎卢胺间隔时间(连续变量)	0.88(0.80~0.97)	＜0.01	0.83(0.72~0.95)	＜0.01
序贯恩扎卢胺前PSA(连续变量)	1.00(0.99~1.001)	0.55
序贯恩扎卢胺前PSA倍增时间(连续变量)	0.86(0.68~1.08)	0.19
序贯恩扎卢胺前NSE^b)
异常vs正常	0.91(0.24~3.48)	0.89
未知vs正常	2.11(0.75~5.98)	0.16
序贯恩扎卢胺时转移情况(高瘤负荷vs寡转移)	0.64(0.24~1.71)	0.37
注：^a)105例患者有BMI数据，31例患者未知; ^b)114例患者有序贯恩扎卢胺前NSE数据，21例患者未知。

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表 3 mHSPC治疗策略分组患者PSM匹配前后临床基线水平比较例(%)，X±S，M(P₂₅，P₇₅)

变量	匹配前			匹配后
变量	阶梯治疗组 (79例)	联合治疗组 (57例)	P值	阶梯治疗组 (57例)	联合治疗组 (57例)	P值
年龄/岁	73.39±8.91	70.53±8.97	0.07	73.19±8.57	70.53±8.97	0.12
GG			0.03			0.15
GG3	18(22.8)	4(7.0)		11(19.3)	4(7.0)
GG4	24(30.4)	17(29.8)		15(26.3)	17(29.8)
GG5	37(46.8)	36(63.2)		31(54.4)	36(63.2)
诊断时PSA/(ng/mL)	154.00 (66.00，335.3)	157.00 (157.00，620.8)	0.49	139.00 (68.00，342.15)	157.00 (63.72，620.80)	0.72
BMI^a)			0.66			0.86
＜25 kg/m²	44(55.7)	30(52.6)		30(52.6)	30(52.6)
≥25 kg/m²	17(21.5)	16(28.1)		14(24.6)	16(28.1)
未知	18(22.8)	11(19.3)		13(22.8)	11(19.3)
临床T分期			0.01			0.07
≤T3a	19(24.1)	3(5.3)		11(19.3)	3(5.3)
T3b	30(38.0)	25(43.9)		23(40.4)	25(43.9)
T4	30(38.0)	29(50.9)		23(40.4)	29(50.9)
临床N分期			＜0.01			0.06
N0	37(46.8)	11(19.3)		21(36.8)	11(19.3)
N1	42(53.2)	46(80.7)		36(63.2)	46(80.7)
临床M分期			0.05			0.28
无转移和寡转移	38(48.1)	18(31.6)		25(43.9)	18(31.6)
高瘤负荷	41(51.9)	39(68.4)		32(56.1)	39(68.4)
阿比特龙治疗进展到序贯恩扎卢胺间隔时间/月	8(3，15)	6(3，9)	0.04	6(3，13.5)	6(3，9)	0.25
阿比特龙治疗时是否进行激素转换			0.87			0.85
否	46(58.2)	34(59.6)		33(57.9)	34(59.6)
是	33(41.8)	23(40.4)		24(42.1)	23(40.4)
转移灶是否接受放疗			0.06			0.27
否	69(87.3)	55(96.5)		51(89.5)	55(96.5)
是	10(12.7)	2(3.5)		6(10.5)	2(3.5)
是否接受化疗			＜0.01			0.27
否	59(74.7)	55(96.5)		51(89.5)	55(96.5)
是	20(25.3)	2(3.5)		6(10.5)	2(3.5)
是否对原发灶进行治疗			0.36			0.56
否	48(60.8)	39(68.4)		35(61.4)	39(68.4)
有	31(39.2)	18(31.6)		22(38.6)	18(31.6)
注：^a)105例患者有BMI数据，31例患者未知。

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表 4 不同mHSPC治疗策略分组PSM匹配后对治疗反应差异例(%)，X±S，M(P₂₅，P₇₅)

变量	阶梯治疗组(57例)	联合治疗组(57例)	P值
阿比特龙治疗最低PSA/(ng/mL)	1.95(0.318，11.41)	0.47(0.10，2.98)	＜0.01
阿比特龙治疗敏感时间/月	7(1，12)	13(8，17.5)	＜0.01
阿比特龙治疗PSA反应率/%	73.29(12.47，91.07)	99.28(95.29，99.93)	＜0.01
序贯恩扎卢胺前PSA/(ng/mL)	18.5(6.14，58.97)	13.4(6.28，81.25)	0.93
序贯恩扎卢胺前PSA倍增时间/月	4.04±2.78	2.51±1.66	＜0.01
序贯恩扎卢胺时转移情况			0.37
无转移和寡转移	15(26.3)	10(17.5)
高瘤负荷	42(73.7)	47(82.5)
序贯恩扎卢胺PSA30			0.06
无	47(82.5)	37(64.9)
有	10(17.5)	20(35.1)
序贯恩扎卢胺PSA50			＜0.01
无	53(93.0)	39(68.4)
有	4(7.0)	18(31.6)

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项目	总人群(136例)	无反应组(111例)	PSA50组(25例)	P值
临床基线特征
年龄/岁	72.19±9.02	72.20±8.88	72.16±9.81	0.98
GG				0.16
GG3	22(16.2)	15(13.5)	7(28.0)
GG4	41(30.1)	36(32.4)	5(20.0)
GG5	73(53.7)	60(54.1)	13(52.0)
诊断时PSA/(ng/mL)	155.75(66.00，353.43)	158(66.00，354.90)	143.00(64.32，459.85)	0.84
BMI/(kg/m²)^a)	23.27(23.27±3.86)	23.21±3.95	23.59±3.44	0.72
临床T分期				0.24
T2	7(5.1)	4(3.6)	3(12.0)
T3a	15(11.0)	14(12.6)	1(4.0)
T3b	58(42.6)	47(42.3)	11(44.0)
T4	56(41.2)	46(41.4)	10(40.0)
临床N分期				0.59
N0	48(35.3)	38(34.2)	10(40.0)
N1	88(64.7)	73(65.8)	15(60.0)
临床M分期				0.37
M0	29(21.3)	22(19.8)	7(28.0)
M1b(转移＜4个转移部位)	27(19.9)	22(19.8)	5(20.0)
M1b(≥4个转移部位且≥1处在椎体和骨盆之外)	69(50.7)	56(50.5)	13(52.0)
M1c	11(8.1)	11(9.9)	0(0)
前线治疗过程
mHSPC阶段治疗策略				＜0.01
阶梯治疗	79(58.1)	72(64.9)	7(28.0)
联合治疗	57(41.9)	39(35.1)	18(72.0)
阿比特龙治疗最低PSA/(ng/mL)	1.36(0.18，7.87)	1.61(0.30，9.18)	0.15(0.054，2.98)	＜0.01
阿比特龙治疗有效时间/月	9(5，14)	8(4，12)	15(12.5，22)	＜0.01
阿比特龙治疗PSA下降率/%	89.86(43.78，99.25)	85.83(30.65，98.56)	99.56(90.64，99.91)	＜0.01
阿比特龙治疗进展到使用恩扎卢胺间隔时间/月	7.00(3.00，13.00)	8.00(4.00，15.00)	4.00(3.00，7.50	＜0.01
阿比特龙治疗时是否进行激素转换				0.56
否	80(58.8)	64(57.7)	16(64.0)
是	56(41.2)	47(42.3)	9(36.0)
转移灶是否接受放疗				0.35
否	124(91.2)	100(90.1)	24(96.0)
是	12(8.8)	11(9.9)	1(4.0)
是否接受多西他赛化疗				0.98
否	114(83.8)	93(83.8)	21(84.0)
是	22(16.2)	18(16.2)	4(16.0)
是否对原发灶进行治疗				0.29
否	79(58.1)	65(58.6)	14(56.0)
前列腺癌根治术	33(24.3)	24(21.6)	9(36.0)
根治性放疗	18(13.2)	16(14.4)	2(8.0)
冷冻治疗	6(4.4)	6(5.4)	0(0)
序贯恩扎卢胺前情况
序贯恩扎卢胺前PSA /(ng/mL)	19.95(6.23，74.92)	20.00(6.34，72.60)	15.5(4.30，123.00)	0.60
序贯恩扎卢胺前PSA倍增时间/月	3.19±2.32	3.32±2.33	2.64±2.27	0.19
序贯恩扎卢胺前NSE/(ng/mL)^b)	13.58(11.07，16.55)	13.50(10.90，16.57)	14.77(12.44，16.75)	0.24
序贯恩扎卢胺前转移情况				0.37
M1b(＜4个转移部位)	29(21.3)	22(19.8)	7(28.0)
M1b(≥4个转移部位且≥1处在椎体和骨盆之外)	92(67.6)	75(67.6)	17(68.0)
M1c	15(11.0)	14(12.6)	1(4.0)
注：前列腺癌分级分组(grade group，GG)。^a)105例患者有BMI数据，其中无反应组89例，PSA50组16例; ^b)114例患者有序贯恩扎卢胺前NSE数据，其中无反应组96例，PSA50组18例。

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阿比特龙序贯恩扎卢胺治疗转移性去势抵抗性前列腺癌临床分析

通讯作者: 李永红，E-mail：liyongh@sysucc.org.cn

Clinical analysis of sequential treatment using abiraterone and enzalutamide for metastatic castration-resistant prostate cancer

Corresponding author: LI Yonghong, E-mail: liyongh@sysucc.org.cn

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阿比特龙序贯恩扎卢胺治疗转移性去势抵抗性前列腺癌临床分析

通讯作者: 李永红，E-mail：liyongh@sysucc.org.cn

Clinical analysis of sequential treatment using abiraterone and enzalutamide for metastatic castration-resistant prostate cancer

Corresponding author: LI Yonghong, E-mail: liyongh@sysucc.org.cn

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