Liang Alyssa, Gulati Shuchi, Huang Quillan, Dowst Heidi, Lim Aedric, Zarrin-Khameh Neda, Godoy Guilherme, Noor Attiya B, Castro Patricia, Scheurer Michael E, Parikh Mamta, Lara Primo N, Hilsenbeck Susan, Mims Martha, Mitsiades Nicholas
Endocr Relat Cancer. 2025 May 29;32(6). doi: 10.1530/ERC-24-0188. Print 2025 Jun 1.
Darolutamide is a second-generation androgen receptor (AR) antagonist (2GARA) with established benefit in treating patients with non-metastatic castration-resistant prostate cancer (M0-CRPC) and metastatic castration-sensitive prostate cancer. Its real-world effectiveness in the treatment of patients with metastatic (M1) CRPC, including those who have progressed on CYP17 inhibitors (CYP17Is) or other 2GARAs (enzalutamide/apalutamide), is not well-described. We assessed the real-world effectiveness of darolutamide in a racially diverse cohort of 44 M1-CRPC and 11 M0-CRPC patients and collected data on baseline and emerging AR mutations in circulating tumor DNA (ctDNA) in these patients. The median progression-free survival (PFS) was 2.15 months for M1-CRPC and 21.16 months for M0-CRPC patients. In the M1-CRPC cohort, the median PFS was longer in those who had only received prior CYP17Is compared to 2GARA-resistant patients (2.43 vs 1.61 months; P = 0.03). Darolutamide suppressed serum PSA levels by >50% in 5/44 M1-CRPC patients (11.4%), all previously 2GARA-naïve. M1-CRPC patients resistant only to CYP17Is had improved mean best percent PSA changes from baseline compared to 2GARA-resistant patients (4.68 vs 42.34%; P = 0.047). PFS was not significantly different between African-American and non-African-American patients, or between patients with and without AR mutations at baseline. AR mutations emerging or increasing in allele fraction in ctDNA upon darolutamide treatment included H875Y, H100Q, D891H, T878A, L702H, L329W, N767Y and AR copy number gain. In summary, darolutamide may provide some benefit in CYP17I-refractory M1-CRPC patients, even in the presence of AR mutations. Resistance to other 2GARAs may significantly decrease benefit from darolutamide.
达洛鲁胺是一种第二代雄激素受体（AR）拮抗剂（2GARA），已证实对治疗非转移性去势抵抗性前列腺癌（M0-CRPC）和转移性去势敏感性前列腺癌患者有益。其在治疗转移性（M1）CRPC患者，包括那些对CYP17抑制剂（CYP17Is）或其他2GARA（恩杂鲁胺/阿帕鲁胺）已进展的患者中的实际疗效尚未得到充分描述。我们评估了达洛鲁胺在44例M1-CRPC和11例M0-CRPC患者的种族多样化队列中的实际疗效，并收集了这些患者循环肿瘤DNA（ctDNA）中基线和新出现的AR突变数据。M1-CRPC患者的无进展生存期（PFS）中位数为2.15个月，M0-CRPC患者为21.16个月。在M1-CRPC队列中，仅接受过CYP17Is治疗的患者的PFS中位数比2GARA耐药患者更长（2.43对1.61个月；P = 0.03）。在44例M1-CRPC患者中有5例（11.4%）血清PSA水平被达洛鲁胺抑制>50%，所有这些患者之前均未使用过2GARA。仅对CYP17Is耐药的M1-CRPC患者与2GARA耐药患者相比，从基线开始的平均最佳PSA变化百分比有所改善（4.68对42.34%；P = 0.047）。非裔美国患者和非非裔美国患者之间，以及基线时有AR突变和无AR突变的患者之间，PFS没有显著差异。达洛鲁胺治疗后ctDNA中出现或等位基因分数增加的AR突变包括H875Y, H100Q, D891H, T878A, L702H, L329W, N767Y和AR拷贝数增加。总之，达洛鲁胺可能对CYP17I难治性M1-CRPC患者有一定益处，即使存在AR突变。对其他2GARA的耐药可能会显著降低达洛鲁胺的益处。
