Rami A, Rashid N S, Zhong C, Xie W, Stoltenberg H, Wheeler E J, Wolanski A, Ritzer J, Choudhury A D, Taplin M-E, Jacene H, Tewari A K, Ravi P
Dana-Farber Cancer Institute, Boston, USA.
Dana-Farber Cancer Institute, Boston, USA; Brigham & Women's Hospital, Boston, USA.
ESMO Open. 2025 Feb;10(2):104131. doi: 10.1016/j.esmoop.2024.104131. Epub 2025 Jan 22.
Lu-prostate-specific membrane antigen (PSMA)-617 (LuPSMA) is a radionuclide therapy approved for patients with PSMA-avid metastatic castrate-resistant prostate cancer (mCRPC). We evaluated whether alterations in the DNA damage repair (DDR) pathway were associated with outcomes to LuPSMA.
We identified an institutional cohort of men (n = 134) treated with ≥2 cycles of LuPSMA who had panel-based germline and/or tumor genomic sequencing. Mutations or two-copy losses in any of BRCA1, BRCA2, ATM, CDK12, PALB2, RAD51, and MSH2 were considered DDR defects. The primary outcome was a ≥50% reduction in the prostate-specific antigen (PSA) level during LuPSMA therapy (PSA50); secondary outcomes were PSA progression-free survival (PSA-PFS) and overall survival (OS). Models were adjusted for age, number of prior systemic therapies, sites of metastasis, and log-transformed PSA at cycle 1.
Thirty-four patients (25%) harbored DDR alterations, most commonly in BRCA2 and ATM (both n = 13). The presence of a DDR defect was not associated with PSA50 [adjusted odds ratio 0.48 (0.20-1.09), P = 0.08], PSA-PFS [adjusted hazard ratio (HR) 1.29 (0.79-2.10), P = 0.30], or OS [adjusted HR 1.42 (0.74-2.72), P = 0.29], with a non-significant trend toward poorer outcomes among DDR-altered patients.
DDR alterations were not associated with outcomes following LuPSMA. This has implications for treatment sequencing in mCRPC, particularly in patients with DDR alterations.
镥标记前列腺特异性膜抗原（PSMA）-617（LuPSMA）是一种已获批用于PSMA阳性转移性去势抵抗性前列腺癌（mCRPC）患者的放射性核素疗法。我们评估了DNA损伤修复（DDR）途径的改变是否与LuPSMA治疗的预后相关。
我们确定了一个机构队列，其中有134名接受过≥2个周期LuPSMA治疗的男性患者，这些患者进行了基于基因panel的种系和/或肿瘤基因组测序。BRCA1、BRCA2、ATM、CDK12、PALB2、RAD51和MSH2中任何一个的突变或双拷贝缺失被视为DDR缺陷。主要结局是LuPSMA治疗期间前列腺特异性抗原（PSA）水平降低≥50%（PSA50）；次要结局是PSA无进展生存期（PSA-PFS）和总生存期（OS）。模型根据年龄、既往全身治疗次数、转移部位以及第1周期时经对数转换的PSA进行了校正。
34例患者（25%）存在DDR改变，最常见于BRCA2和ATM（均为n = 13）。DDR缺陷的存在与PSA50[校正比值比0.48（0.20-1.09），P = 0.08]、PSA-PFS[校正风险比（HR）1.29（0.79-2.10），P = 0.30]或OS[校正HR 1.42（0.74-2.72），P = 0.29]均无关，DDR改变的患者预后较差的趋势不显著。
DDR改变与LuPSMA治疗后的预后无关。这对mCRPC的治疗顺序有影响，特别是对存在DDR改变的患者。
