Ont Health Technol Assess Ser. 2023 Aug 10;23(5):1-188. eCollection 2023.
Ovarian cancer affects the cells of the ovaries, and epithelial cancer is the most common type of malignant ovarian cancer. The homologous recombination repair pathway enables error-free repair of DNA double-strand breaks. Damage of key genes associated with this pathway leads to homologous recombination deficiency (HRD), which results in unrepaired DNA and can lead to cancer. Tumours with HRD are believed to be sensitive to treatment with poly-adenosine diphosphate (ADP)-ribose polymerase (PARP) inhibitors, such as niraparib. We conducted a health technology assessment to evaluate the clinical utility and cost-effectiveness of HRD testing to inform patient decisions about the use of niraparib maintenance therapy for patients with high-grade serous or endometrioid epithelial ovarian cancer. We also evaluated the efficacy and safety of niraparib maintenance therapy in patients with HRD or homologous recombination proficiency (HRP), the cost-effectiveness of HRD testing, the budget impact of publicly funding HRD testing, and patient preferences and values.
We performed a systematic literature search of the clinical evidence. We assessed the risk of bias of each included study using the Cochrane risk-of-bias tool for randomized trials version 2, and the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We performed a systematic economic literature search and conducted a cost-utility analysis with a 5-year time horizon from a public payer perspective. We also analyzed the budget impact of publicly funding HRD testing in people with ovarian cancer in Ontario. We performed a literature search for quantitative evidence of patient and provider preferences with respect to HRD testing and maintenance therapy with PARP inhibitors. To contextualize the potential value of HRD testing, we spoke with people with ovarian cancer.
The clinical evidence review included two studies in high-grade epithelial ovarian cancer (one in patients with newly diagnosed advanced cases and one in patients with recurrent cancer). The studies evaluated niraparib maintenance therapy compared with no maintenance therapy and used HRD testing to group patients according to HRD status. Compared to placebo, niraparib maintenance therapy improved progression-free survival in patients with newly diagnosed and recurrent ovarian cancer, and in tumours with HRD or HRP (GRADE: High), but the studies did not compare the results between the HRD and HRP groups. The frequency of adverse events was higher in the niraparib group. We identified no studies that evaluated the clinical utility of HRD testing.We conducted a primary economic evaluation to evaluate the cost-effectiveness of HRD testing for people with newly diagnosed ovarian cancer in an Ontario setting. Our analysis used a 5-year time horizon. HRD testing (for all eligible people or only for people with wild type) resulted in a lower proportion of patients receiving niraparib maintenance therapy, leading to lower costs and fewer quality-adjusted life-years (QALYs). The average total cost per patient was $131,375 for no HRD testing, $126,867 for HRD testing only in people with wild type, and $127,746 for HRD testing in all eligible people. The average total QALYs per patient were 2.087 for no HRD testing, 1.971 for HRD testing only in people with wild type, and 1.971 for HRD testing in all eligible people. Our budget impact analysis suggested that assuming a high uptake rate, publicly funding HRD testing for people with newly diagnosed ovarian cancer would lead to a total saving of $9.00 million (if HRD testing were funded for all) to $12.67 million (if HRD testing were funded for people with wild type) over the next 5 years. Publicly funding HRD testing for people with recurrent cancer would lead to a total saving of $16.31 million (if HRD testing were funded for all) to $21.67 million (if HRD testing were funded for people with wild type) over the next 5 years.We identified no studies that evaluated quantitative preferences for HRD testing. Based on two studies that evaluated patients and oncologists' preferences for maintenance therapy with a PARP inhibitor in the recurrent setting, a decrease in moderate to severe adverse events was more important for patients than an improvement in progression-free survival; however, improvement in progression-free survival was more important for oncologists. Both patients and oncologists accepted some trade-offs between efficacy and safety. The people with ovarian cancer we spoke with demonstrated a shared value for access to information, prevention of cancer recurrence, and overall survival with minimal adverse effects. This was consistent with findings from another survey in patients with ovarian cancer and at least one episode of recurrence, which suggest that patients prioritize treatment benefit over some treatment adverse events in the context of niraparib maintenance therapy. Interviewees also emphasized the importance of the patient-doctor partnership, access to local health care services, and patient education.
In patients with newly diagnosed (advanced) or recurrent high-grade serous or endometrioid ovarian cancer, niraparib maintenance therapy improved progression-free survival compared with no maintenance therapy in tumours with HRD or HRP (GRADE: High). Because we identified no studies on the clinical utility of HRD testing, we cannot comment on how it would affect patient decisions and clinical outcomes.Over a 5-year time horizon, HRD testing for people with wild type could save $4,509 per person and lead to a loss of 0.116 QALY. The findings of our economic analyses are dependent on assumptions about the use of niraparib following HRD testing. We estimate that publicly funding HRD testing would lead to a total saving of $9 million to $12.67 million for newly diagnosed cancer, and a total saving of $16.31 million to $21.67 million for recurrent cancer over 5 years, assuming the use of niraparib maintenance therapy would be reduced following HRD testing.Patients prioritized decreasing the risk of moderate to severe adverse events of maintenance therapy with PARP inhibitors over improving progression-free survival, and oncologists prioritized improving progression-free survival over decreasing the risk of moderate to severe adverse events. However, both patients and oncologists were open to accepting certain trade-offs between treatment efficacy and toxicity. The people we interviewed, who had lived experience with ovarian cancer and genetic testing, valued the potential clinical benefits of HRD testing for themselves and their family members. They emphasized patient education as an important consideration for public funding in Ontario.
卵巢癌影响卵巢细胞，上皮癌是最常见的恶性卵巢癌类型。同源重组修复途径使 DNA 双链断裂得到无差错修复。与该途径相关的关键基因的损伤导致同源重组缺陷（HRD），导致未修复的 DNA，并可能导致癌症。据信，具有 HRD 的肿瘤对聚腺苷二磷酸（ADP）-核糖聚合酶（PARP）抑制剂（如尼拉帕利）的治疗敏感。我们进行了一项卫生技术评估，以评估 HRD 检测在告知患者使用尼拉帕利维持治疗高级别浆液性或子宫内膜样上皮性卵巢癌中的应用决策方面的临床实用性和成本效益。我们还评估了 HRD 或同源重组能力（HRP）患者中尼拉帕利维持治疗的疗效和安全性、HRD 检测的成本效益、公开资助 HRD 检测的预算影响，以及患者偏好和价值观。
我们对临床证据进行了系统的文献检索。我们使用 Cochrane 对随机试验版本 2 的偏倚风险工具评估了每项纳入研究的偏倚风险，并根据 Grading of Recommendations Assessment, Development, and Evaluation（GRADE）工作组标准评估了证据体的质量。我们进行了系统的经济文献检索，并从公共支付者的角度进行了为期 5 年的成本效用分析。我们还分析了在安大略省对卵巢癌患者进行 HRD 检测的预算影响。我们对有关 HRD 检测和 PARP 抑制剂维持治疗的患者和提供者偏好的定量证据进行了文献检索。为了使 HRD 检测的潜在价值具有现实意义，我们与患有卵巢癌的患者进行了交谈。
临床证据综述包括两项高级上皮性卵巢癌的研究（一项针对新诊断的晚期病例，另一项针对复发性癌症）。这些研究评估了尼拉帕利维持治疗与无维持治疗相比，以及使用 HRD 检测根据 HRD 状态对患者进行分组。与安慰剂相比，尼拉帕利维持治疗可改善新诊断和复发性卵巢癌患者的无进展生存期，以及 HRD 或 HRP 患者（GRADE：高），但这些研究并未比较 HRD 和 HRP 组之间的结果。尼拉帕利组的不良反应频率更高。我们没有发现评估 HRD 检测临床实用性的研究。我们进行了一项主要的经济评估，以评估在安大略省新诊断卵巢癌患者中进行 HRD 检测的成本效益。我们的分析使用了 5 年的时间范围。HRD 检测（对所有合格患者或仅对野生型患者）导致接受尼拉帕利维持治疗的患者比例降低，从而降低了成本和较少的质量调整生命年（QALYs）。每位患者的平均总成本为 131375 美元，不进行 HRD 检测，126867 美元进行 HRD 检测仅适用于野生型患者，127746 美元进行 HRD 检测适用于所有合格患者。每位患者的平均总 QALYs 为 2.087 个，不进行 HRD 检测，1.971 个仅适用于野生型患者，1.971 个适用于所有合格患者。我们的预算影响分析表明，假设高吸收率，公开资助新诊断卵巢癌患者的 HRD 检测将在未来 5 年内节省 900 万美元（如果对所有患者进行 HRD 检测）至 1267 万美元（如果对野生型患者进行 HRD 检测）。公开资助复发性癌症患者的 HRD 检测将在未来 5 年内节省 1631 万美元（如果对所有患者进行 HRD 检测）至 2167 万美元（如果对野生型患者进行 HRD 检测）。我们没有发现评估 HRD 检测定量偏好的研究。基于两项评估复发性环境中 PARP 抑制剂维持治疗患者和肿瘤学家偏好的研究，与改善无进展生存期相比，减少中度至重度不良事件对患者更为重要；然而，改善无进展生存期对肿瘤学家更为重要。患者和肿瘤学家都接受了在疗效和安全性之间进行一些权衡。我们交谈过的卵巢癌患者表现出对获得信息、预防癌症复发和整体生存的共同价值，同时尽量减少不良影响。这与另一项针对至少有一次复发的卵巢癌患者的调查结果一致，该调查表明，在尼拉帕利维持治疗的背景下，患者优先考虑治疗获益，而不是一些治疗不良反应。受访者还强调了患者-医生合作关系、获得当地医疗服务和患者教育的重要性。
在新诊断（晚期）或复发性高级别浆液性或子宫内膜样卵巢癌患者中，与无维持治疗相比，尼拉帕利维持治疗可改善 HRD 或 HRP 患者的无进展生存期（GRADE：高）。由于我们没有发现评估 HRD 检测临床实用性的研究，因此我们无法评论它将如何影响患者决策和临床结果。在 5 年的时间范围内，对野生型患者进行 HRD 检测可能会使每个人节省 4509 美元，并导致 0.116 个 QALY 损失。我们经济分析的结果取决于 HRD 检测后使用尼拉帕利维持治疗的假设。我们估计，公开资助 HRD 检测将为新诊断癌症节省 900 万美元至 1267 万美元，为复发性癌症节省 1631 万美元至 2167 万美元，假设 HRD 检测后将减少尼拉帕利维持治疗的使用。患者优先考虑降低 PARP 抑制剂维持治疗的中度至重度不良反应的风险，而不是改善无进展生存期，肿瘤学家优先考虑改善无进展生存期，而不是降低中度至重度不良反应的风险。然而，患者和肿瘤学家都愿意接受治疗效果和毒性之间的某些权衡。我们采访的人患有卵巢癌并有基因检测的经验，他们重视 HRD 检测对自己和家人的潜在临床益处。他们强调，在安大略省，患者教育是公共资助的一个重要考虑因素。
