A Phase II Trial of Abiraterone With Dutasteride for Second‐Generation Antiandrogen‐ and Chemotherapy‐Na?ve Patients With Castration‐Resistant Prostate Cancer
A Phase II Trial of Abiraterone With Dutasteride for Second‐Generation Antiandrogen‐ and Chemotherapy‐Na?ve Patients With Castration‐Resistant Prostate Cancer
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阿比特龙联合度他雄胺治疗未接受过第二代抗雄激素治疗和化疗的去势抵抗性前列腺癌患者的 II 期试验
DOI：
10.1002/jcph.2191
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Matsuyama Hideyasu
中科院分区：
文献类型：
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作者：
Shiota Masaki;Inoue Ryo;Tashiro Kojiro;Kobayashi Keita;Horiyama Shizuyo;Kanji Hiromi;Eto Masatoshi;Egawa Shin;Haginaka Jun;Matsuyama Hideyasu
开发一种克服对阿比特龙的原发性和获得性耐药性的新疗法是一种未满足的需求。本研究旨在评价在阿比特龙基础上添加5α-还原酶抑制剂度他雄胺的疗效和安全性，探索概念验证，并确定适合联合治疗的候选药物。这项II期、单组、开放标签研究入组了第二代抗雄激素和化疗初治的去势抵抗性前列腺癌患者。患者接受阿比特龙和泼尼松龙治疗4周，然后加用度他雄胺。主要终点是50%的前列腺特异性抗原应答率。测定阿比特龙及其代谢产物的血药浓度以及HSD 3B 1和SRD 5A 2基因型。评估药物代谢和基因型之间的关联及其对联合治疗疗效的影响。在21例患者中，18例（85.7%）PSA降低≥50%。在15.4个月的中位随访期间，未达到至治疗失败的中位时间。无患者发生≥3级不良事件。尽管度他雄胺降低了血清3-酮-5 α-阿比特龙浓度，但联合治疗时血清3-酮-5 α-阿比特龙浓度较高与治疗失败时间较短相关。添加度他雄胺前，HSD 3B 1和SRD 5A 2基因型分别与血清Δ4-阿比特龙和3-酮-5 α-阿比特龙浓度相关。纯合子野生型HSD 3B 1患者的治疗失败时间较长，但与SRD 5A 2基因型患者相似。本研究的良好结果值得在随机试验中进一步研究联合治疗。根据HSD 3B 1和SRD 5A 2基因谱进行分层可能有助于确定适合联合治疗的患者。
The development of a novel therapy to overcome primary and acquired resistance to abiraterone is an unmet need. This study aimed to evaluate the efficacy and safety of adding 5α‐reductase inhibitor dutasteride to abiraterone, explore proof of concept, and identify candidates suitable for combination therapy. This phase II, single‐arm, and open‐label study enrolled second‐generation antiandrogen‐ and chemotherapy‐naïve patients with castration‐resistant prostate cancer. Patients received abiraterone and prednisolone for 4 weeks, followed by adding dutasteride. The primary end point was a 50% prostate‐specific antigen response rate. Serum concentrations of abiraterone and its metabolites as well asHSD3B1andSRD5A2genotypes were measured. The association between drug metabolism and genotypes and their impact on the efficacy of combination therapy were assessed. Among 21 patients, 18 (85.7%) achieved ≥50% PSA reduction. Median time to treatment failure was not reached during the median follow‐up of 15.4 months. No patients experienced grade ≥3 adverse events. Although dutasteride reduced serum 3‐keto‐5α‐abiraterone concentrations, higher serum 3‐keto‐5α‐abiraterone concentrations on combination therapy were associated with a shorter time to treatment failure.HSD3B1andSRD5A2genotypes were associated with serum Δ4‐abiraterone and 3‐keto‐5α‐abiraterone concentrations before adding dutasteride, respectively. Time to treatment failure was longer in patients with homozygous wild‐typeHSD3B1, but comparable between those with theSRD5A2genotype. The promising outcomes of this study warrant further investigation of combination therapy in a randomized trial. Stratification byHSD3B1andSRD5A2genetic profiles might identify patients suitable for combination therapy.