Lessons learned: The combination of standard dose abiraterone acetate and BEZ235, a pan-class I PI3K and mTORC1/2 inhibitor, was poorly tolerated in men with progressive mCRPC.Although the clinical development of BEZ235 has been discontinued in prostate cancer, agents that more selectively target PI3K-AKT-mTOR signaling may have a more favorable therapeutic index and should continue to be explored.
Background: Androgen receptor (AR) and phosphatidylinositol-3 kinase (PI3K) signaling are two commonly perturbed pathways in prostate cancer. Preclinical data have shown that the two pathways compensate for each other when one is inhibited, and combined inhibition of AR and PI3K signaling may be a viable strategy to prevent or overcome castration resistance.
Methods: This phase I study evaluated the safety and tolerability of abiraterone acetate and prednisone combined with BEZ235, a dual PI3K and mTORC1/2 inhibitor, in men with progressive metastatic castration resistant prostate cancer (mCRPC) who have not received prior chemotherapy.
Results: Six patients (n = 6) were treated at the starting dose level of abiraterone acetate 1,000 mg with prednisone 5 mg twice daily and BEZ235 200 mg twice daily in a 3 + 3 dose escalation design. The study was terminated early because three of the six patients (50%) experienced dose-limiting toxicities: grade 3 mucositis, grade 3 hypotension, and grade 4 dyspnea and pneumonitis. All six patients had previously progressed on abiraterone/prednisone. The median treatment duration was 27 days (range: 3-130 days). No prostate-specific antigen (PSA) decline or objective response were observed.
Conclusion: The combination of standard-dose abiraterone/prednisone with BEZ235 200 mg twice daily was poorly tolerated in patients with mCRPC. The on-target and off-target effects of dual PI3K and mTORC inhibition likely contributed to the unacceptable toxicity profile. The Oncologist 2017;22:503-e43.
经验总结
• 在疾病进展的mCRPC患者中, 标准剂量的醋酸阿比特龙与泛I类PI3K和mTORC1/2抑制剂BEZ235联合用药的耐受性较差。
• 虽然BEZ235治疗前列腺癌的临床开发现已终止, 但以PI3K‐AKT‐mTOR信号通路为靶点的高度选择性药物可能具有更为理想的治疗指数, 应继续进行探索。
摘要
背景. 雄激素受体(AR)和磷脂酰肌醇‐3激酶(PI3K)信号通路是前列腺癌中常发生紊乱的两条通路。临床前数据表明, 如果两条通路的其中之一受到抑制, 二者可相互补偿;因此, 同时抑制AR和PI3K信号通路可能是防止或克服去势抵抗性的一种可行策略。
方法. 本项I期研究在既往未接受过化疗的转移性去势抵抗性前列腺癌(mCRPC)进展患者中评价了醋酸阿比特龙和泼尼松与PI3K和mTORC1/2双重抑制剂BEZ235联用的安全性和耐受性。
结果. 6例患者(n=6)按照3 + 3剂量递增设计接受起始剂量水平的醋酸阿比特龙(1 000 mg)、泼尼松(5 mg每日两次)和BEZ235(200 mg每日两次)联合治疗。6例患者中有3例(50%)出现剂量限制性毒性(3级黏膜炎、3级低血压以及4级呼吸困难和非感染性肺炎), 故本研究被提前终止。所有6例患者既往接受阿比特龙/泼尼松治疗时均出现疾病进展。中位治疗持续时间为27天(范围:3‐130天)。未观察到前列腺特异性抗原(PSA)降低或客观缓解。
结论. 标准剂量的阿比特龙/泼尼松与BEZ235 200 mg每日两次联合给药在mCRPC患者中耐受性较差。PI3K和mTORC双重抑制的靶向和脱靶效应可能会产生不可接受的毒性。The Oncologist 2017;22:503–e43
Trial registration: ClinicalTrials.gov NCT01717898.
© AlphaMed Press; the data published online to support this summary is the property of the authors.