Shiota Masaki, Inoue Ryo, Tashiro Kojiro, Kobayashi Keita, Horiyama Shizuyo, Kanji Hiromi, Eto Masatoshi, Egawa Shin, Haginaka Jun, Matsuyama Hideyasu
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Japan.
J Clin Pharmacol. 2023 Apr;63(4):445-454. doi: 10.1002/jcph.2191. Epub 2023 Jan 17.
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 as HSD3B1 and SRD5A2 genotypes 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. HSD3B1 and SRD5A2 genotypes 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-type HSD3B1, but comparable between those with the SRD5A2 genotype. The promising outcomes of this study warrant further investigation of combination therapy in a randomized trial. Stratification by HSD3B1 and SRD5A2 genetic profiles might identify patients suitable for combination therapy.
开发一种新型疗法以克服对阿比特龙的原发性和获得性耐药是一项尚未满足的需求。本研究旨在评估在阿比特龙中添加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、单臂、开放标签研究纳入了未接受过第二代抗雄激素和化疗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，随后添加度他雄胺。主要终点是50%的前列腺特异性抗原反应率。测量了阿比特龙及其代谢物的血清浓度以及HSD3B1和SRD5A2基因型。评估了药物代谢与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%）实现了≥50%的PSA降低。在15.4个月的中位随访期间未达到治疗失败的中位时间。没有患者发生≥3级不良事件。尽管度他雄胺降低了血清3-酮-5α-阿比特龙浓度，但联合治疗时较高的血清3-酮-5α-阿比特龙浓度与较短的治疗失败时间相关。HSD3B1和SRD5A2基因型分别与添加度他雄胺前的血清Δ4-阿比特龙和3-酮-5α-阿比特龙浓度相关。纯合野生型HSD3B1患者的治疗失败时间较长，但SRD5A2基因型患者之间的治疗失败时间相当。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HSD3B1和SRD5A2基因谱进行分层可能会识别出适合联合治疗的患者。
