Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
Department of Biostatistics, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Eur Urol. 2021 May;79(5):692-699. doi: 10.1016/j.eururo.2020.06.042. Epub 2020 Jul 2.
Cyclic high-dose testosterone injections, also known as bipolar androgen therapy (BAT), is a novel treatment strategy for patients with metastatic castration-resistant prostate cancer (mCRPC). BAT has shown clinical activity in prior studies enrolling men with mCRPC and may potentially restore sensitivity to prior androgen receptor (AR)-targeted agents.
To evaluate the clinical activity of BAT in patients progressing on AR-targeted therapy as well as responses to abiraterone or enzalutamide upon rechallenge after BAT.
DESIGN, SETTING, AND PARTICIPANTS: RESTORE is a multicohort phase II study enrolling asymptomatic mCRPC patients after abiraterone or enzalutamide at Johns Hopkins Hospital (NCT02090114). Participants (29 after abiraterone and 30 after enzalutamide) received 400 mg testosterone cypionate intramuscularly every 28 days, with ongoing luteinizing hormone-releasing hormone agonist/antagonist treatment (ie, BAT). Following progression on BAT, patients were rechallenged with their most recent AR-targeted therapy.
Coprimary endpoints were >50% decline in PSA from baseline (PSA) responses to BAT and following AR-targeted therapy rechallenge. Outcomes in the post-abiraterone cohort are presented, as well as updated results from the post-enzalutamide cohort and an exploratory AR-V7 analysis.
No statistically significant difference in PSA response rates to BAT was observed (30% [post-enzalutamide cohort] vs 17% [post-abiraterone cohort], p = 0.4). However, PSA responses to AR-targeted therapy rechallenge were higher in the post-enzalutamide cohort (68% vs 16%, p = 0.001). The median time from enrollment to progression following rechallenge with AR-targeted therapy (ie, progression-free survival 2; PFS2) was longer in the post-enzalutamide versus post-abiraterone patients (12.8 vs 8.1 mo, p = 0.04). Outcomes were worse in patients with detectable AR-V7 in circulating tumor cells (median PFS2: 10.3 vs 7.1 mo, p = 0.005).
BAT shows clinical activity in mCRPC patients and may be more effective at resensitizing to enzalutamide versus abiraterone.
BAT is well tolerated in metastatic castration-resistant prostate cancer patients. The type of prior AR-targeted therapy might affect response to BAT as well as AR-therapy rechallenge. BAT followed by AR-targeted therapy rechallenge did not improve outcomes in AR-V7-positive patients.
周期性高剂量睾酮注射，也称为双相雄激素治疗（BAT），是一种治疗转移性去势抵抗性前列腺癌（mCRPC）患者的新策略。在既往入组 mCRPC 男性的研究中，BAT 显示出了临床活性，并且可能有潜力恢复对既往雄激素受体（AR）靶向药物的敏感性。
评估 BAT 在接受 AR 靶向治疗后进展的患者中的临床活性，以及在 BAT 后重新接受阿比特龙或恩扎卢胺的反应。
设计、地点和参与者：RESTORE 是一项多队列 II 期研究，在约翰霍普金斯医院入组接受阿比特龙或恩扎卢胺治疗后的无症状 mCRPC 患者（NCT02090114）。参与者（阿比特龙后 29 例，恩扎卢胺后 30 例）每 28 天接受 400mg 醋酸环丙孕酮肌内注射，同时持续使用促黄体生成素释放激素激动剂/拮抗剂治疗（即 BAT）。在 BAT 进展后，患者重新接受最近的 AR 靶向治疗。
主要终点是 BAT 治疗后和重新接受 AR 靶向治疗后 PSA 从基线下降≥50%（PSA）反应。仅报告阿比特龙后队列的结果，以及恩扎卢胺后队列的更新结果和探索性的 AR-V7 分析。
BAT 治疗后的 PSA 反应率无统计学显著差异（阿比特龙后队列为 30%，恩扎卢胺后队列为 17%，p=0.4）。然而，恩扎卢胺后队列中重新接受 AR 靶向治疗后的 PSA 反应率更高（68% vs 16%，p=0.001）。与恩扎卢胺后队列相比，重新接受 AR 靶向治疗后无进展生存期 2（即无进展生存期 2；PFS2）的时间更长（中位时间分别为 12.8 个月和 8.1 个月，p=0.04）。在循环肿瘤细胞中检测到 AR-V7 的患者中，结局更差（中位 PFS2：10.3 个月 vs 7.1 个月，p=0.005）。
BAT 在 mCRPC 患者中显示出临床活性，并且在重新敏化方面可能比阿比特龙更有效。
BAT 在转移性去势抵抗性前列腺癌患者中耐受良好。既往 AR 靶向治疗的类型可能会影响 BAT 反应以及 AR 治疗重新挑战。BAT 后重新接受 AR 靶向治疗并未改善 AR-V7 阳性患者的结局。
