Rathkopf D E, Patel M R, Choudhury A D, Rasco D, Lakhani N, Hawley J E, Srinivas S, Aparicio A, Narayan V, Runcie K D, Emamekhoo H, Reichert Z R, Nguyen M H, Wells A L, Kandimalla R, Liu C, Suryawanshi S, Han J, Wu J, Arora V K, Pourdehnad M, Armstrong A J
Memorial Sloan Kettering Cancer Center, New York.
Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota.
Ann Oncol. 2025 Jan;36(1):76-88. doi: 10.1016/j.annonc.2024.09.005. Epub 2024 Sep 16.
Metastatic castration-resistant prostate cancer (mCRPC) that progresses on androgen receptor pathway inhibitors (ARPIs) may continue to be driven by AR signaling. BMS-986365 is an orally administered ligand-directed degrader targeting the AR via a first-in-class dual mechanism of AR degradation and antagonism. CC-94676-PCA-001 (NCT04428788) is a phase I multicenter study of BMS-986365 in patients with progressive mCRPC.
Patients who progressed on androgen deprivation therapy, one or more ARPIs, and taxane chemotherapy (unless declined/ineligible) were enrolled. The study included dose escalation (part A) and expansion (part B) of BMS-986365 up to 900 mg twice daily. Primary objectives were safety and tolerability, and to define maximum tolerated dose and/or recommended phase II dose. Key secondary endpoints included decline in prostate-specific antigen ≥50% (PSA50) and radiographic progression-free survival (rPFS).
Parts A and B enrolled 27 and 68 patients, respectively. In part B, the median number of prior therapies was 4 (range 2-11). The most common treatment-related adverse events were asymptomatic prolonged corrected QT interval (47%) and bradycardia (34%). Part A maximum tolerated dose was not reached and recommended phase II dose selection is ongoing. Across part B three highest doses (400-900 mg twice daily, n = 60), PSA50 was 32% (n = 19), including 50% (n = 10/20) at 900 mg; median rPFS (95% confidence interval) was 6.3 months (5.3-12.6 months), including 8.3 months (3.8-16.6 months) at 900 mg; and rPFS was longer in patients without versus with prior chemotherapy: 16.5 months (5.5 months-not evaluable) versus 5.5 months (2.7-8.3 months), respectively. Efficacy was observed in patients with mCRPC with AR ligand binding domain (LBD) WT or with AR LBD mutations.
BMS-986365 was well tolerated, with a manageable safety profile, and demonstrated activity in heavily pretreated patients with mCRPC with potentially higher benefit in chemotherapy-naive patients. These data show the potential of BMS-986365 to overcome resistance to current ARPIs, regardless of AR LBD mutation status.
在雄激素受体通路抑制剂（ARPI）治疗期间进展的转移性去势抵抗性前列腺癌（mCRPC）可能仍由AR信号驱动。BMS-986365是一种口服的配体导向降解剂，通过一流的AR降解和拮抗双重机制靶向AR。CC-94676-PCA-001（NCT04428788）是一项关于BMS-986365治疗进展性mCRPC患者的I期多中心研究。
纳入在雄激素剥夺治疗、一种或多种ARPI以及紫杉烷化疗（除非拒绝/不符合条件）期间进展的患者。该研究包括BMS-986365剂量递增（A部分）和扩展（B部分），最高剂量为每日两次900mg。主要目标是安全性和耐受性，确定最大耐受剂量和/或推荐的II期剂量。关键次要终点包括前列腺特异性抗原下降≥50%（PSA50）和影像学无进展生存期（rPFS）。
A部分和B部分分别纳入27例和68例患者。在B部分，既往治疗的中位数为4次（范围2-11次）。最常见的治疗相关不良事件是无症状的校正QT间期延长（47%）和心动过缓（34%）。未达到A部分的最大耐受剂量，推荐的II期剂量选择正在进行中。在B部分的三个最高剂量组（每日两次400-900mg，n=60）中，PSA50为32%（n=19），其中900mg时为50%（n=10/20）；中位rPFS（95%置信区间）为6.3个月（5.3-12.6个月），其中900mg时为8.3个月（3.8-16.6个月）；未接受过化疗的患者的rPFS长于接受过化疗的患者：分别为16.5个月（不可评估-5.5个月）和5.5个月（2.7-8.3个月）。在具有AR配体结合域（LBD）野生型或AR LBD突变的mCRPC患者中观察到疗效。
BMS-986365耐受性良好，安全性可控，在经过大量治疗的mCRPC患者中显示出活性，对未接受过化疗的患者可能有更高的获益。这些数据显示了BMS-986365克服对当前ARPI耐药的潜力，无论AR LBD突变状态如何。
