Raychaudhuri Ruben, Cheng Heather H, Gulati Roman, Schweizer Michael T, Lin Aaron, Yezefski Todd, Khan Hiba M, Yu Evan Y, Hawley Jessica E, Nelson Peter S, Pritchard Colin C, Montgomery Bruce
Division of Hematology and Oncology, University of Washington, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Eur Urol Oncol. 2025 May 23. doi: 10.1016/j.euo.2025.04.026.
Our aim was to determine whether induction chemotherapy followed by PARP inhibitor (PARPi) maintenance improves outcomes for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring alterations in homologous recombination repair (HRR) genes in comparison to a historical control cohort treated with PARPi monotherapy.
This single-arm, open-label, investigator-initiated phase 2 trial (NCT02985021) enrolled 18 patients with mCRPC with pathogenic alterations in HRR genes between 2018 and 2021 at a single center. Patients received four cycles of induction chemotherapy with docetaxel (60 mg/m) and carboplatin (area under the curve 5) every 21 d, followed by maintenance rucaparib (600 mg twice daily) until progression or unacceptable toxicity. The primary outcome was radiographic progression-free survival (rPFS). Subsequent to study inception, multiple other studies reported alterations in genes of the BRCA complex (BRCA-C: BRCA1, BRCA2, PALB2) as most predictive of PARPi response; therefore, a post hoc analysis comparing patients with alterations in BRCA-C genes to a historical control cohort was performed.
After median follow-up of 40.3 mo (interquartile range 38.5-not reached [NR]), the median rPFS for all patients was 8.1 mo (95% confidence interval [CI] 6.5-31.2), similar to a historical control cohort treated with PARPi monotherapy. Among the 12 patients with BRCA-C alterations, median rPFS was 17.7 mo (95% CI 7.5-NR; p = 0.05). A key limitation is the single-arm design.
Induction platinum-based chemotherapy followed by maintenance PARPi therapy did not improve outcomes for patients with mCRPC broadly selected for HRR deficiency. However, results were promising in the more stringently selected group with BRCA-C gene alterations. Further studies comparing this approach to PARPi monotherapy are warranted.
我们的目的是确定与接受聚（腺苷酸-核糖）聚合酶抑制剂（PARPi）单药治疗的历史对照队列相比，诱导化疗后使用PARPi维持治疗是否能改善同源重组修复（HRR）基因发生改变的转移性去势抵抗性前列腺癌（mCRPC）患者的预后。
这项单臂、开放标签、研究者发起的2期试验（NCT02985021）于2018年至2021年在一个中心纳入了18例HRR基因发生致病性改变的mCRPC患者。患者接受四个周期的多西他赛（60mg/m²）和卡铂（曲线下面积5）诱导化疗，每21天一次，随后接受鲁卡帕尼维持治疗（600mg，每日两次），直至病情进展或出现不可接受的毒性。主要结局是影像学无进展生存期（rPFS）。在研究开始后，多项其他研究报告称，BRCA复合体（BRCA-C：BRCA1、BRCA2、PALB2）基因改变最能预测PARPi反应；因此，进行了一项事后分析，将BRCA-C基因发生改变的患者与历史对照队列进行比较。
中位随访40.3个月（四分位间距38.5 - 未达到[NR]）后，所有患者的中位rPFS为8.1个月（95%置信区间[CI] 6.5 - 31.2），与接受PARPi单药治疗的历史对照队列相似。在12例BRCA-C改变的患者中，中位rPFS为17.7个月（95% CI 7.5 - NR；p = 0.05）。一个关键局限性是单臂设计。
对于广泛选择的HRR缺陷的mCRPC患者，诱导铂类化疗后使用PARPi维持治疗并未改善预后。然而，在选择更严格的BRCA-C基因改变组中，结果很有前景。有必要进一步开展研究，将这种方法与PARPi单药治疗进行比较。
