双极性雄激素治疗（BAT）导致睾酮（T）在接近去势水平和超生理水平之间快速波动，并在转移性去势抵抗性前列腺癌（mCRPC）中显示出前途。其临床效果可能通过诱导DNA损伤介导，临床前研究表明与PARP抑制剂有协同作用。这是一项单中心二期试验，测试olaparib加上BAT（T丙酸酯/戊酸酯400毫克，每28天一次），并继续进行雄激素剥夺。计划招募30名mCRPC患者，其中一半有/没有同源重组修复[HRR]基因突变，并在经过奥比安硷和/或恩扎鲁胺后采用。主要目标是确定12周内PSA50反应率（PSA从基线下降≥50％）。主要分析使用整个（意图治疗[ITT]）队列，早期退出者被视为非反应者。二次/探索性分析是在治疗超过12周的患者中进行的（反应可评估队列）。共有36名患者入组，6名在反应评估之前退出。在ITT队列中，12周后的PSA50反应率为11/36（31％；95％CI 17-48％），在任何时候在研究中16/36（44％，95％CI 28-62％）有PSA50反应。经过中位随访19个月后，ITT队列中的中位临床/放射性无进展生存期为13.0个月（95％CI 7-17）。无论HRR基因突变状态如何，临床结果都相似。BAT加olaparib与高反应率和长PFS相关。观察到临床获益，无论HRR基因突变状态如何。 © 2022年。作者（独家许可Springer Nature Limited）。

Bipolar androgen therapy (BAT) results in rapid fluctuation of testosterone (T) between near-castrate and supraphysiological levels and has shown promise in metastatic castration-resistant prostate cancer (mCRPC). Its clinical effects may be mediated through induction of DNA damage, and preclinical studies suggest synergy with PARP inhibitors.This was a single-center, Phase II trial testing olaparib plus BAT (T cypionate/enanthate 400 mg every 28 days) with ongoing androgen deprivation. Planned recruitment was 30 subjects (equal proportions with/without homologous recombination repair [HRR] gene mutations) with mCRPC post abiraterone and/or enzalutamide. The primary objective was to determine PSA50 response (PSA decline ≥50% from baseline) rate at 12-weeks. The primary analysis utilized the entire (intent-to-treat [ITT]) cohort, with those dropping out early counted as non-responders. Secondary/exploratory analyses were in those treated beyond 12-weeks (response-evaluable cohort).Thirty-six patients enrolled and 6 discontinued prior to response assessment. In the ITT cohort, PSA50 response rate at 12-weeks was 11/36 (31%; 95% CI 17-48%), and 16/36 (44%, 95% CI 28-62%) had a PSA50 response at any time on-study. After a median follow-up of 19 months, the median clinical/radiographic progression-free survival in the ITT cohort was 13.0 months (95% CI 7-17). Clinical outcomes were similar regardless of HRR gene mutational status.BAT plus olaparib is associated with high response rates and long PFS. Clinical benefit was observed regardless of HRR gene mutational status.© 2022. The Author(s), under exclusive licence to Springer Nature Limited.