Supplementary Material for: Preliminary efficacy, tolerability, and safety analysis of Darolutamide for metastatic castration‑resistant prostate cancer: a single-center, open-label study

Purpose: Darolutamide is a structurally unique second-generation androgen receptor antagonist that has been approved for indications in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and metastatic hormone-sensitive prostate cancer (mHSPC). The aim is to assess the efficacy and safety of Darolutamide for mCRPC.
Methods: In this single-center, open-label, phase 1 study, patients with previously untreated mCRPC were enrolled and received androgen deprivation therapy (ADT, goserelin acetate 3.6 mg every 28 days) and docetaxel (75 mg per square meter of body surface area every 21 days) with Denosumab (120 mg every 28 days) for bone metastases, Darolutamide (300 mg orally twice daily) in the experimental group, and the control group received the corresponding of placebo. Serum PSA changes were detected and recorded, and imaging changes and adverse events (AEs) were evaluated. The primary endpoints were the safety, tolerability, and antitumor efficacy and the second endpoint was the radiographic progression-free survival (rPFS).
Results: 37 patients with mCRPC were enrolled. The median time to PSA50 in the Darolutamide group was 1.5 months (95%CI 0.2619- 0.9545), significantly lower than that in the placebo group (3.0 months [95%CI 1.048- 3.818], p= 0.0259); The median time to PSA90 in the experimental group was 4 months (95%CI 0.3094- 1.437), 2 months shorter than that in the placebo group (6.0 months [95%CI 0.6961- 3.232]).With the median follow-up of 6 months, , the median decrease in serum PSA was -81.8% (range -60.4 to -99.9%) in the Darolutamide group and -69.4% (range -50.3 to -89.6%) in the placebo group. Tumor-related pain and AEs were not increased and the median rPFS was not reach.
Conclusions: The combination of Darolutamide and docetaxel was well tolerated with more clinically beneficial than docetaxel alone in previously untreated mCRPC. Darolutamide rapidly reduced PSA levels and prolonged rPFS, and did not increase the incidence of AEs.

研究目的：达罗他胺（Darolutamide）是一种结构独特的第二代雄激素受体拮抗剂，已获批用于非转移性去势抵抗性前列腺癌（non-metastatic castration-resistant prostate cancer, nmCRPC）与转移性激素敏感性前列腺癌（metastatic hormone-sensitive prostate cancer, mHSPC）的临床适应症。本研究旨在评估达罗他胺针对转移性去势抵抗性前列腺癌（metastatic castration-resistant prostate cancer, mCRPC）的疗效与安全性。

研究方法：本研究为单中心、开放标签的1期临床试验，纳入既往未经治疗的mCRPC患者。实验组患者接受雄激素剥夺治疗（androgen deprivation therapy, ADT，醋酸戈舍瑞林（goserelin acetate）3.6mg，每28天1次）、多西他赛（docetaxel，75mg/体表面积，每21天1次）、骨转移治疗用药地诺单抗（Denosumab，120mg，每28天1次），同时口服达罗他胺300mg，每日2次；对照组则给予对应安慰剂。研究人员检测并记录血清前列腺特异性抗原（prostate-specific antigen, PSA）水平变化，同时评估影像学改变与不良事件（adverse events, AEs）。本研究的主要终点为安全性、耐受性及抗肿瘤疗效，次要终点为影像学无进展生存期（radiographic progression-free survival, rPFS）。

研究结果：本研究共纳入37例mCRPC患者。达罗他胺组患者达到PSA50的中位时间为1.5个月（95%CI 0.2619~0.9545），显著低于安慰剂组的3.0个月（95%CI 1.048~3.818，p=0.0259）；实验组患者达到PSA90的中位时间为4个月（95%CI 0.3094~1.437），较安慰剂组的6.0个月（95%CI 0.6961~3.232）缩短2个月。中位随访6个月时，达罗他胺组患者血清PSA的中位降幅为-81.8%（范围：-60.4%~-99.9%），安慰剂组为-69.4%（范围：-50.3%~-89.6%）。两组均未出现肿瘤相关疼痛及不良事件发生率升高的情况，且中位rPFS尚未达到。

研究结论：达罗他胺联合多西他赛的治疗方案耐受性良好，相较于单纯多西他赛治疗，可为既往未经治疗的mCRPC患者带来更显著的临床获益。达罗他胺可快速降低PSA水平，延长rPFS，且未增加不良事件的发生率。