Johns Hopkins University School of Medicine, Baltimore, Maryland.
University of Nebraska Medical Center, Omaha.
JAMA Oncol. 2024 Oct 1;10(10):1400-1408. doi: 10.1001/jamaoncol.2024.3074.
Olaparib is a poly(adenosine diphosphate-ribose) polymerase inhibitor that provides benefit in combination with hormonal therapies in patients with metastatic prostate cancer who harbor homologous recombination repair (HRR) alterations. Its efficacy in the absence of androgen deprivation therapy has not been tested.
To determine the activity of olaparib monotherapy among patients with high-risk biochemically recurrent (BCR) prostate cancer after radical prostatectomy.
DESIGN, SETTING, AND PARTICIPANTS: This phase 2, single-arm nonrandomized controlled trial enrolled genetically unselected patients across 4 sites in the US from May 2017 to November 2022. Eligible patients had BCR disease following radical prostatectomy, a prostate-specific antigen (PSA) doubling time of 6 months or shorter, an absolute PSA value of 1.0 ng/mL or higher, and a testosterone level of 150 ng/dL or higher.
Treatment was with olaparib, 300 mg, by mouth twice daily until doubling of the baseline PSA, clinical or radiographic progression, or unacceptable toxic effects.
The primary end point was a confirmed 50% or higher decline in PSA from baseline (PSA50). Key secondary end points were outcomes by HRR alteration status, as well as safety and tolerability.
Of the 51 male patients enrolled (mean [SD] age, 63.8 [6.8] years), 13 participants (26%) had a PSA50 response, all within the HRR-positive group (13 of 27 participants [48%]). All 11 participants with BRCA2 alterations experienced a PSA50 response. Common adverse events were fatigue in 32 participants (63%), nausea in 28 (55%), and leukopenia in 22 (43%), and were consistent with known adverse effects of olaparib.
In this nonrandomized controlled trial, olaparib monotherapy led to high and durable PSA50 response rates in patients with BRCA2 alterations. Olaparib warrants further study as a treatment strategy for some patients with BCR prostate cancer but does not have sufficient activity in those without HRR alterations and should not be considered for those patients.
ClinicalTrials.gov Identifier: NCT03047135.
奥拉帕利是一种聚（腺苷二磷酸核糖）聚合酶抑制剂，与激素治疗联合使用可使携带同源重组修复（HRR）改变的转移性前列腺癌患者获益。其在没有去势治疗的情况下的疗效尚未得到检验。
确定奥拉帕利单药治疗根治性前列腺切除术后高危生化复发（BCR）前列腺癌患者的疗效。
设计、地点和参与者：这是一项在美国 4 个地点进行的 2 期、单臂、非随机对照临床试验，于 2017 年 5 月至 2022 年 11 月期间纳入了未经基因选择的患者。入组患者为根治性前列腺切除术后发生 BCR 疾病、前列腺特异性抗原（PSA）倍增时间为 6 个月或更短、绝对 PSA 值为 1.0ng/mL 或更高、且睾酮水平为 150ng/dL 或更高的患者。
治疗方法是给予奥拉帕利，300mg，口服，每日 2 次，直至 PSA 基线倍增、临床或影像学进展或不可接受的毒性作用。
主要终点为 PSA 自基线下降 50%或更多（PSA50）的确认应答。关键次要终点为 HRR 改变状态的结果，以及安全性和耐受性。
共纳入 51 名男性患者（平均[SD]年龄，63.8[6.8]岁），其中 13 名患者（26%）PSA50 应答，均在 HRR 阳性组（27 名患者中的 13 名[48%]）。所有 11 名存在 BRCA2 改变的患者均出现 PSA50 应答。常见的不良反应为乏力（32 名患者[63%]）、恶心（28 名[55%]）和白细胞减少（22 名[43%]），这些不良反应与已知的奥拉帕利不良反应一致。
在这项非随机对照试验中，奥拉帕利单药治疗在存在 BRCA2 改变的患者中产生了高且持久的 PSA50 应答率。奥拉帕利作为 BCR 前列腺癌患者的一种治疗策略具有一定的潜力，但在没有 HRR 改变的患者中疗效有限，不适合用于这些患者，不应考虑用于这些患者。
ClinicalTrials.gov 标识符：NCT03047135。
