Division of Hematology and Oncology, University of Washington, Seattle, WA.
Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA.
JCO Precis Oncol. 2024 Apr;8:e2300634. doi: 10.1200/PO.23.00634.
While Lu-PSMA-617 (LuPSMA) is an effective therapy for many patients with metastatic castration-resistant prostate cancer (mCRPC), biomarkers associated with outcomes are not well defined. We hypothesized that prostate cancer mutational profile may associate with clinical activity of LuPSMA. We devised a study to evaluate associations between mCRPC mutational profile with LuPSMA clinical outcomes.
This was a multicenter retrospective analysis of patients with mCRPC with next-generation sequencing (NGS) who received LuPSMA. PSA response (ie, ≥50% decline in prostate-specific antigen [PSA]) rate, PSA progression free survival (PSA PFS), and overall survival (OS) were compared between genetically defined subgroups.
One hundred twenty-six patients with NGS results who received at least one cycle of LuPSMA were identified. The median age was 73 (IQR, 68-78) years, 124 (98.4%) received ≥1 prior androgen receptor-signaling inhibitor, and 121 (96%) received ≥1 taxane-based chemotherapy regimen. Fifty-eight (46%) patients with a DNA damage repair gene mutation (DNA damage response group) and 59 (46.8%) with a mutation in , , or tumor suppressor genes (TSG group) were identified. After adjusting for relevant confounders, the presence of ≥1 TSG mutation was associated with shorter PSA PFS (hazard ratio [HR], 1.93 [95% CI, 1.05 to 3.54]; = .034) and OS (HR, 2.65 [95% CI, 1.15 to 6.11]; = .023). There was improved OS favoring the DNA damage response group (HR, 0.37 [95% CI, 0.14 to 0.97]; = .044) on multivariable analysis. Univariate analysis of patients with mutations had significantly higher rates of PSA response, PSA PFS, and OS.
Outcomes on LuPSMA varied on the basis of mutational profile. Prospective studies to define the clinical activity of LuPSMA in predefined genomic subgroups are justified.
虽然 Lu-PSMA-617（LuPSMA）是许多转移性去势抵抗性前列腺癌（mCRPC）患者的有效治疗方法，但与疗效相关的生物标志物尚不清楚。我们假设前列腺癌突变谱可能与 LuPSMA 的临床活性相关。我们设计了一项研究来评估 mCRPC 突变谱与 LuPSMA 临床结果之间的关联。
这是一项多中心回顾性分析，纳入了接受 LuPSMA 治疗的 mCRPC 患者的下一代测序（NGS）结果。比较了基因定义亚组之间的前列腺特异性抗原（PSA）应答率（即 PSA 下降≥50%）、PSA 无进展生存期（PSA PFS）和总生存期（OS）。
确定了 126 名接受至少一个周期 LuPSMA 治疗且具有 NGS 结果的患者。中位年龄为 73（IQR，68-78）岁，124 名（98.4%）患者接受了≥1 种雄激素受体信号抑制剂治疗，121 名（96%）患者接受了≥1 种紫杉烷类化疗方案。确定了 58 名（46%）有 DNA 损伤修复基因突变（DNA 损伤反应组）和 59 名（46.8%）有 、 或 肿瘤抑制基因（TSG 组）突变的患者。在调整了相关混杂因素后，≥1 个 TSG 突变的存在与较短的 PSA PFS（风险比 [HR]，1.93 [95%CI，1.05 至 3.54]；.034）和 OS（HR，2.65 [95%CI，1.15 至 6.11]；.023）相关。多变量分析显示，DNA 损伤反应组的 OS 改善（HR，0.37 [95%CI，0.14 至 0.97]；.044）。在有 突变的患者中，PSA 应答率、PSA PFS 和 OS 显著更高。
根据突变谱，LuPSMA 的疗效不同。有理由进行前瞻性研究，以确定 LuPSMA 在预先定义的基因组亚组中的临床活性。
