Chi Kim N, Castro Elena, Attard Gert, Smith Matthew R, Sandhu Shahneen, Efstathiou Eleni, Roubaud Guilhem, Small Eric J, de Santana Gomes Andrea Pereira, Rathkopf Dana E, Saad Marniza, Gurney Howard, Jung Wonho, Kim Won, Dibaj Shiva, Wu Daphne, Zhang Jenny, Lopez-Gitlitz Angela, Francis Peter, Olmos David
BC Cancer-Vancouver, University of British Columbia, Vancouver, Canada.
Department of Medical Oncology, Hospital Universitario 12 de Octubre. Instituto de Investigación Sanitaria Hospital 12 de Octubre, Madrid, Spain.
Eur Urol Oncol. 2025 May 5. doi: 10.1016/j.euo.2025.04.012.
The phase 3 MAGNITUDE trial previously met its primary endpoint of an improvement in radiographic progression-free survival with niraparib + abiraterone acetate and prednisone (AAP) versus placebo + AAP in patients with metastatic castration-resistant prostate cancer (mCRPC) and alterations in genes involved in DNA homologous recombination repair (HRR), particularly in BRCA1/2.
Patients were prospectively screened for HRR alterations and randomized 1:1 to niraparib + AAP (n = 212) or placebo + AAP (n = 211). We report results from the prespecified, event-driven, final analysis of secondary efficacy endpoints.
Final analysis at median follow-up of 37.3 mo revealed no difference in overall survival (OS) between niraparib + AAP and placebo + AAP in the HRR population (hazard ratio [HR] 0.931, 95% confidence interval [CI] 0.720-1.203; p = 0.585) or the subgroup with BRCA1/2 alterations (HR 0.788, 95% CI 0.554-1.120; nominal p = 0.183). Prespecified multivariate analyses adjusted for baseline prognostic factors showed a trend toward longer OS with niraparib + AAP over placebo + AAP in the HRR population (HR 0.785, 95% CI 0.606-1.016; nominal p = 0.066) and the BRCA1/2 subgroup (HR 0.663, 95% CI 0.464-0.947; nominal p = 0.024). Niraparib + AAP led to a statistically significant, clinically meaningful improvement in time to symptomatic progression in both the HRR population (HR 0.547, 95% CI 0.396-0.754; p = 0.006) and the BRCA1/2 subgroup (HR 0.562, 95% CI 0.371-0.849; nominal p = 0.006), and a clinically meaningful improvement in time to cytotoxic chemotherapy in the HRR population (HR 0.688, 95% CI 0.499-0.950; p = 0.022) and the BRCA1/2 subgroup (HR 0.598, 95% CI 0.387-0.924; nominal p = 0.019) in comparison to placebo + AAP. The niraparib + AAP safety profile remains unchanged at longer follow-up; adverse events were primarily hematologic and manageable.
The MAGNITUDE final analysis showed that patients with HRR mCRPC, including those with the approved indication of BRCA-altered mCRPC, generally continue to benefit from first-line treatment with niraparib + AAP in comparison to placebo + AAP.
3期MAGNITUDE试验先前已达到其主要终点，即对于转移性去势抵抗性前列腺癌（mCRPC）且DNA同源重组修复（HRR）相关基因存在改变、尤其是BRCA1/2基因改变的患者，与安慰剂+醋酸阿比特龙和泼尼松（AAP）相比，尼拉帕利+AAP可改善影像学无进展生存期。
对患者进行前瞻性HRR改变筛查，并按1:1随机分为尼拉帕利+AAP组（n = 212）或安慰剂+AAP组（n = 211）。我们报告预先设定的、事件驱动的次要疗效终点最终分析结果。
在中位随访37.3个月时进行的最终分析显示，在HRR人群中，尼拉帕利+AAP组与安慰剂+AAP组的总生存期（OS）无差异（风险比[HR] 0.931，95%置信区间[CI] 0.720 - 1.203；p = 0.585），在BRCA1/2改变亚组中也无差异（HR 0.788，95% CI 0.554 - 1.120；名义p = 0.183）。针对基线预后因素进行预先设定的多变量分析显示，在HRR人群中，尼拉帕利+AAP组的OS有长于安慰剂+AAP组的趋势（HR 0.785，95% CI 0.606 - 1.016；名义p = 0.066），在BRCA1/2亚组中也是如此（HR 0.663，95% CI 0.464 - 0.947；名义p = 0.024）。与安慰剂+AAP相比，尼拉帕利+AAP使HRR人群（HR 0.547，95% CI 0.396 - 0.754；p = 0.006）和BRCA1/2亚组（HR 0.562，95% CI 0.371 - 0.849；名义p = 0.006）出现症状进展时间有统计学显著且具有临床意义的改善，并且使HRR人群（HR 0.688, 95% CI 0.499 - 0.950；p = 0.022）和BRCA1/2亚组（HR 0.598，95% CI 0.387 - 0.924；名义p = 0.019）接受细胞毒性化疗时间有临床意义的改善。尼拉帕利+AAP的安全性在更长随访期内保持不变；不良事件主要为血液学方面且可控制。
MAGNITUDE最终分析表明，与安慰剂+AAP相比，HRR mCRPC患者，包括那些具有BRCA改变的mCRPC这一获批适应症的患者，通常继续从尼拉帕利+AAP一线治疗中获益。
