Connell Brendan, Hwang Clara, Folefac Edmund, Lawlor Christian, Koethe Benjamin, Mathew Paul
Department of Hematology & Oncology, Tufts Medical Center, Boston, MA; Division of Hematology & Oncology, Lahey Hospital & Medical Center, Burlington, MA.
Hematology/Oncology Division, Henry Ford Health, Detroit, MI.
Clin Genitourin Cancer. 2025 Aug;23(4):102368. doi: 10.1016/j.clgc.2025.102368. Epub 2025 Apr 29.
Disease progression in castration-resistant prostate cancer (CRPC) remains bone-dominant and docetaxel-responsive. Docetaxel and radium-223 would be a logical combination but myelosuppression is dose-limiting. Dose-dense schedules of docetaxel have comparable activity to bolus dosing with mitigated myelosuppression. We hypothesized that dose-dense docetaxel with standard radium-223 would be a feasible, safe and effective combination in bone-dominant metastatic CRPC.
Subjects had progressive bone-predominant CRPC. Design was dose escalation plus expansion with 28-day cycles. Docetaxel was given every 2 weeks in a 4-week lead-in, then with Radium-223 every 4 weeks up to 6 cycles. Dose-levels (DL) included 1: docetaxel 40 mg/m; 1a: docetaxel 40 mg/m with G-CSF on Day 16, 2a: docetaxel 50 mg/m with G-CSF on Day 16. The maximum tolerated dose (MTD) was defined as the highest (DL) of docetaxel achieved without dose-limiting toxicity (DLT). Markers of safety and efficacy were annotated.
Forty-three subjects were enrolled (NCT03737370). The patient population included 21% black, 9% Asians, 93% had prior intensified hormonal therapy, 67% had bone pain, and 76% had ≥ 4 bone metastases. Seven patients dropped out during the 4-week docetaxel lead in. Neutropenia at DL 1 limited combination therapy. No (DLT) occurred at DL 1a (n = 6) or DL 2a (n = 5). Twenty-two patients were enrolled to an expansion cohort with docetaxel 50 mg/m with G-CSF on Day 16 (DL 2a), the designated MTD. Among 35 patients treated with the combination, there were no febrile neutropenia events. One patient had dose-limiting Grade 3 anemia. PSA50 response was 51.4% and PSA90 was 25.7%. Median progression-free survival was 11.7 months, and median overall survival was 20.1 months.
A lead-in cycle and a dose-dense schedule of docetaxel with G-CSF enabled the combination with radium-223 in standard dose-intensities with minimal hematological toxicity. The regimen will likely combine logically and safely with hormone-intensification for study in high-risk/high-volume castration-sensitive metastatic disease.
去势抵抗性前列腺癌（CRPC）的疾病进展仍以骨转移为主且对多西他赛有反应。多西他赛和镭-223可能是合理的联合用药，但骨髓抑制是剂量限制性毒性。多西他赛的密集给药方案与大剂量给药活性相当，但骨髓抑制减轻。我们假设，在以骨转移为主的转移性CRPC中，密集剂量的多西他赛与标准剂量的镭-223联合使用将是一种可行、安全且有效的组合。
受试者患有以骨转移为主的进展性CRPC。设计为剂量递增加扩展，每28天为一个周期。多西他赛在4周的导入期每2周给药一次，然后每4周与镭-223联合给药，最多6个周期。剂量水平（DL）包括：1：多西他赛40mg/m²；1a：多西他赛40mg/m²，第16天给予粒细胞集落刺激因子（G-CSF）；2a：多西他赛50mg/m²，第16天给予G-CSF。最大耐受剂量（MTD）定义为在无剂量限制性毒性（DLT）情况下达到的多西他赛最高（DL）。记录安全性和有效性指标。
共纳入43名受试者（NCT03737370）。患者群体包括21%的黑人、9%的亚洲人，93%曾接受过强化激素治疗，67%有骨痛，76%有≥4处骨转移。7名患者在4周的多西他赛导入期退出。DL1时的中性粒细胞减少限制了联合治疗。DL1a（n = 6）或DL2a（n = 5）未发生（DLT）。22名患者入组扩展队列，接受第16天给予G-CSF的多西他赛50mg/m²（DL2a），即指定的MTD。在接受联合治疗的35名患者中，未发生发热性中性粒细胞减少事件。1名患者出现剂量限制性3级贫血。PSA50缓解率为51.4%，PSA90缓解率为25.7%。中位无进展生存期为11.7个月，中位总生存期为20.1个月。
多西他赛的导入周期和密集给药方案联合G-CSF，使得多西他赛能与标准剂量强度的镭-223联合使用，血液学毒性最小。该方案可能与激素强化治疗合理、安全地联合，用于高危/高负荷去势敏感性转移性疾病的研究。
