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Abstract：
BACKGROUND: The activity of PARP inhibitors (PARPi) in patients with homologous recombination repair (HRR) mutations and metastatic castration-resistant prostate cancer has been established. We hypothesized that the benefit of PARPi can be maintained in the absence of androgen deprivation therapy (ADT) in an HRR-mutated population. We report the results of a phase II clinical trial of rucaparib monotherapy in patients with metastatic hormone-sensitive prostate cancer (mHSPC).
METHODS: This was a multi-center, single-arm phase II trial (NCT03413995) for patients with asymptomatic, mHSPC. Patients were required to have a pathogenic germline mutation in an HRR gene for eligibility. All patients received rucaparib 600 mg by mouth twice daily, without androgen deprivation. The primary endpoint was a confirmed PSA50 response rate.
RESULTS: Twelve patients were enrolled, 7 with a BRCA1/2 mutation and 5 with a CHEK2 mutation. The confirmed PSA50 response rate to rucaparib was 41.7% (N = 5/12, 95% CI: 15.2-72.3%, one-sided P = .81 against the 50% null), which did not meet the pre-specified efficacy boundary to enroll additional patients. In patients with measurable disease, the objective response rate was 60% (N = 3/5), all with a BRCA2 mutation. The median radiographic progression-free survival on rucaparib was estimated at 12.0 months (95% CI: 8.0-NR months). The majority of adverse events were grade ≤2, and expected.
CONCLUSIONS: Rucaparib can induce clinical responses in a biomarker-selected metastatic prostate cancer population without concurrent ADT. However, the pre-specified efficacy threshold was not met, and enrolment was truncated. Although durable responses were observed in a subset of patients, further study of PARPi treatment without ADT in mHSPC is unlikely to change clinical practice.
METHODS: This was a multi-center, single-arm phase II trial (NCT03413995) for patients with asymptomatic, mHSPC. Patients were required to have a pathogenic germline mutation in an HRR gene for eligibility. All patients received rucaparib 600 mg by mouth twice daily, without androgen deprivation. The primary endpoint was a confirmed PSA50 response rate.
RESULTS: Twelve patients were enrolled, 7 with a BRCA1/2 mutation and 5 with a CHEK2 mutation. The confirmed PSA50 response rate to rucaparib was 41.7% (N = 5/12, 95% CI: 15.2-72.3%, one-sided P = .81 against the 50% null), which did not meet the pre-specified efficacy boundary to enroll additional patients. In patients with measurable disease, the objective response rate was 60% (N = 3/5), all with a BRCA2 mutation. The median radiographic progression-free survival on rucaparib was estimated at 12.0 months (95% CI: 8.0-NR months). The majority of adverse events were grade ≤2, and expected.
CONCLUSIONS: Rucaparib can induce clinical responses in a biomarker-selected metastatic prostate cancer population without concurrent ADT. However, the pre-specified efficacy threshold was not met, and enrolment was truncated. Although durable responses were observed in a subset of patients, further study of PARPi treatment without ADT in mHSPC is unlikely to change clinical practice.
摘要：
背景：已经确定了PARP抑制剂（PARPi）在同源重组修复（HRR）突变和转移性去势抵抗性前列腺癌患者中的活性。我们假设PARPi的益处可以在没有雄激素剥夺治疗（ADT）的情况下在HRR突变的人群中保持。我们报告了rucaparib单药治疗转移性激素敏感性前列腺癌（mHSPC）患者的II期临床试验的结果。
方法：这是一个多中心，针对无症状患者的单臂II期试验（NCT03413995），mHSPC。患者需要在HRR基因中具有致病性种系突变以获得资格。所有患者每天两次口服600毫克rucaparib，没有雄激素剥夺。主要终点是确认的PSA50应答率。
结果：纳入12例患者，7具有BRCA1/2突变和5具有CHEK2突变。对rucaparib的确认PSA50反应率为41.7％（N=5/12，95％CI：15.2-72.3％，单侧P=0.81对50%为零)，不符合预先指定的疗效界限以纳入其他患者。在患有可测量疾病的患者中，客观反应率为60%(N=3/5)，都有BRCA2突变。rucaparib的中位无进展生存期估计为12.0个月(95%CI:8.0-NR个月)。大多数不良事件为≤2级，并且是预期的。
结论：Rucaparib可以在没有并发ADT的生物标志物选择的转移性前列腺癌人群中诱导临床反应。然而,未达到预先指定的疗效阈值，注册被截断。尽管在一部分患者中观察到了持久的反应，mHSPC中无ADT的PARPi治疗的进一步研究不太可能改变临床实践.
方法：这是一个多中心，针对无症状患者的单臂II期试验（NCT03413995），mHSPC。患者需要在HRR基因中具有致病性种系突变以获得资格。所有患者每天两次口服600毫克rucaparib，没有雄激素剥夺。主要终点是确认的PSA50应答率。
结果：纳入12例患者，7具有BRCA1/2突变和5具有CHEK2突变。对rucaparib的确认PSA50反应率为41.7％（N=5/12，95％CI：15.2-72.3％，单侧P=0.81对50%为零)，不符合预先指定的疗效界限以纳入其他患者。在患有可测量疾病的患者中，客观反应率为60%(N=3/5)，都有BRCA2突变。rucaparib的中位无进展生存期估计为12.0个月(95%CI:8.0-NR个月)。大多数不良事件为≤2级，并且是预期的。
结论：Rucaparib可以在没有并发ADT的生物标志物选择的转移性前列腺癌人群中诱导临床反应。然而,未达到预先指定的疗效阈值，注册被截断。尽管在一部分患者中观察到了持久的反应，mHSPC中无ADT的PARPi治疗的进一步研究不太可能改变临床实践.
