Abstract：
High-risk prostate cancer (PCa) patients have a high risk of biochemical recurrence and metastatic progression following radical prostatectomy (RP).
To determine the efficacy of neoadjuvant degarelix plus apalutamide before RP compared with degarelix with a matching placebo.
ARNEO was a randomized, placebo-controlled, phase II neoadjuvant trial before RP performed between March 2019 and April 2021. Eligible patients had high-risk PCa and were amenable to RP.
Patients were randomly assigned at a 1:1 ratio to degarelix (240-80-80 mg) + apalutamide (240 mg/d) versus degarelix + matching placebo for 3 mo followed by RP. Prior to and following neoadjuvant treatment, pelvic 18F-PSMA-1007 positron emission tomography (PET)/magnetic resonance imaging (MRI) was performed.
The primary endpoint was the difference in proportions of patients with minimal residual disease (MRD; = residual cancer burden (RCB) ≤0.25 cm3 at final pathology). Secondary endpoints included differences in prostate-specific antigen responses, pathological staging, and change in TNM stage on prostate-specific membrane antigen (PSMA) PET/MRI following hormonal treatment. Biomarkers (immunohistochemical staining on prostate biopsy [PTEN, ERG, Ki67, P53, GR, and PSMA] and PSMA PET/MRI-derived characteristics) associated with pathological response (MRD and RCB) were explored.
Patients were randomized to neoadjuvant degarelix + apalutamide (n = 45) or degarelix + matching placebo (n = 44) for 12 wk and underwent RP. Patients in the degarelix + apalutamide arm achieved a significantly higher rate of MRD than those in the control arm (38% vs 9.1%; relative risk [95% confidence interval] = 4.2 [1.5-11], p = 0.002). Patients with PTEN loss in baseline prostate biopsy attained significantly less MRD (11% vs 43%, p = 0.002) and had a higher RCB at final pathology (1.6 vs 0.40 cm3, p < 0.0001) than patients without PTEN loss. Following neoadjuvant hormonal therapy, PSMA PET-estimated tumor volumes (1.2 vs 2.5 ml, p = 0.01) and maximum standardized uptake value (SUVmax; 4.3 vs 5.7, p = 0.007) were lower in patients with MRD than in patients without MRD. PSMA PET-estimated volume and PSMA PET SUVmax following neoadjuvant treatment correlated significantly with RCB at final pathology (both p < 0.001).
In high-risk PCa patients, neoadjuvant degarelix plus apalutamide prior to RP results in a significantly improved pathological response (MRD and RCB) compared with degarelix alone. Our trial results provide a solid hypothesis-generating basis for neoadjuvant phase 3 trials, which are powered to detect differences in long-term oncological outcome following neoadjuvant androgen receptor signaling inhibitor therapy.
In this study, we looked at the difference in pathological responses in high-risk prostate cancer patients treated with degarelix plus apalutamide or degarelix plus matching placebo prior to radical prostatectomy. We demonstrated that patients treated with degarelix plus apalutamide achieved a significantly better tumor response than patients treated with degarelix plus matching placebo. Long-term follow-up is required to determine whether improved pathological outcome translates into better oncological outcomes.
To determine the efficacy of neoadjuvant degarelix plus apalutamide before RP compared with degarelix with a matching placebo.
ARNEO was a randomized, placebo-controlled, phase II neoadjuvant trial before RP performed between March 2019 and April 2021. Eligible patients had high-risk PCa and were amenable to RP.
Patients were randomly assigned at a 1:1 ratio to degarelix (240-80-80 mg) + apalutamide (240 mg/d) versus degarelix + matching placebo for 3 mo followed by RP. Prior to and following neoadjuvant treatment, pelvic 18F-PSMA-1007 positron emission tomography (PET)/magnetic resonance imaging (MRI) was performed.
The primary endpoint was the difference in proportions of patients with minimal residual disease (MRD; = residual cancer burden (RCB) ≤0.25 cm3 at final pathology). Secondary endpoints included differences in prostate-specific antigen responses, pathological staging, and change in TNM stage on prostate-specific membrane antigen (PSMA) PET/MRI following hormonal treatment. Biomarkers (immunohistochemical staining on prostate biopsy [PTEN, ERG, Ki67, P53, GR, and PSMA] and PSMA PET/MRI-derived characteristics) associated with pathological response (MRD and RCB) were explored.
Patients were randomized to neoadjuvant degarelix + apalutamide (n = 45) or degarelix + matching placebo (n = 44) for 12 wk and underwent RP. Patients in the degarelix + apalutamide arm achieved a significantly higher rate of MRD than those in the control arm (38% vs 9.1%; relative risk [95% confidence interval] = 4.2 [1.5-11], p = 0.002). Patients with PTEN loss in baseline prostate biopsy attained significantly less MRD (11% vs 43%, p = 0.002) and had a higher RCB at final pathology (1.6 vs 0.40 cm3, p < 0.0001) than patients without PTEN loss. Following neoadjuvant hormonal therapy, PSMA PET-estimated tumor volumes (1.2 vs 2.5 ml, p = 0.01) and maximum standardized uptake value (SUVmax; 4.3 vs 5.7, p = 0.007) were lower in patients with MRD than in patients without MRD. PSMA PET-estimated volume and PSMA PET SUVmax following neoadjuvant treatment correlated significantly with RCB at final pathology (both p < 0.001).
In high-risk PCa patients, neoadjuvant degarelix plus apalutamide prior to RP results in a significantly improved pathological response (MRD and RCB) compared with degarelix alone. Our trial results provide a solid hypothesis-generating basis for neoadjuvant phase 3 trials, which are powered to detect differences in long-term oncological outcome following neoadjuvant androgen receptor signaling inhibitor therapy.
In this study, we looked at the difference in pathological responses in high-risk prostate cancer patients treated with degarelix plus apalutamide or degarelix plus matching placebo prior to radical prostatectomy. We demonstrated that patients treated with degarelix plus apalutamide achieved a significantly better tumor response than patients treated with degarelix plus matching placebo. Long-term follow-up is required to determine whether improved pathological outcome translates into better oncological outcomes.
摘要：
背景：高危前列腺癌（PCa）患者在根治性前列腺切除术（RP）后生化复发和转移进展的风险很高。
目的：确定RP前替加瑞利加阿帕鲁胺新辅助治疗与替加瑞利加匹配安慰剂的疗效。
方法：ARNEO是随机的，安慰剂对照,2019年3月至2021年4月进行RP前的II期新辅助试验。符合条件的患者患有高危PCa，并且适合RP。
方法：患者以1：1的比例随机分配给地加瑞克（240-80-80mg）阿帕鲁胺（240mg/d）与地加瑞克匹配的安慰剂3个月，然后进行RP。在新辅助治疗之前和之后，进行盆腔18F-PSMA-1007正电子发射断层扫描（PET）/磁共振成像（MRI）。
方法：主要终点是微小残留病变患者的比例差异（MRD；=最终病理时残留癌症负荷（RCB）≤0.25cm3）。次要终点包括前列腺特异性抗原反应的差异，病理分期,激素治疗后前列腺特异性膜抗原（PSMA）PET/MRI的TNM分期变化。生物标志物（前列腺活检的免疫组织化学染色[PTEN，ERG,Ki67,P53,GR,和PSMA]和PSMAPET/MRI衍生的特征）与病理反应（MRD和RCB）相关。
结论：患者随机接受地加瑞利+阿帕鲁胺（n=45）或地加瑞利+匹配安慰剂（n=44）治疗12周，并接受RP治疗。地加瑞克+阿帕鲁胺组患者的MRD发生率明显高于对照组患者（38%vs9.1%；相对危险度[95%置信区间]=4.2[1.5-11]，p=0.002)。在基线前列腺活检中PTEN丢失的患者获得了显著较低的MRD(11%vs43%,p=0.002），并且在最终病理时的RCB高于无PTEN丢失的患者（1.6vs0.40cm3，p<0.0001）。新辅助激素治疗后，PSMAPET估计的肿瘤体积（1.2对2.5ml，MRD患者的p=0.01）和最大标准化摄取值（SUVmax;4.3vs5.7，p=0.007）低于无MRD患者。新辅助治疗后PSMAPET估计体积和PSMAPETSUVmax与最终病理时的RCB显著相关(均p<0.001)。
结论：在高危PCa患者中，与单独使用地加瑞利相比,在RP之前新辅助地加阿帕鲁胺可显著改善病理反应(MRD和RCB).我们的试验结果为新辅助治疗3期试验提供了坚实的假设生成基础，它们能够检测新辅助雄激素受体信号传导抑制剂治疗后长期肿瘤结局的差异。
结果：在这项研究中，我们观察了在前列腺癌根治术前接受地加瑞利加阿帕鲁胺或地加瑞利加配伍安慰剂治疗的高危前列腺癌患者的病理反应差异.我们证明，使用地加瑞克加阿帕鲁胺治疗的患者比使用地加瑞克加匹配安慰剂治疗的患者获得了显着更好的肿瘤反应。需要长期随访以确定改善的病理结果是否转化为更好的肿瘤结果。
目的：确定RP前替加瑞利加阿帕鲁胺新辅助治疗与替加瑞利加匹配安慰剂的疗效。
方法：ARNEO是随机的，安慰剂对照,2019年3月至2021年4月进行RP前的II期新辅助试验。符合条件的患者患有高危PCa，并且适合RP。
方法：患者以1：1的比例随机分配给地加瑞克（240-80-80mg）阿帕鲁胺（240mg/d）与地加瑞克匹配的安慰剂3个月，然后进行RP。在新辅助治疗之前和之后，进行盆腔18F-PSMA-1007正电子发射断层扫描（PET）/磁共振成像（MRI）。
方法：主要终点是微小残留病变患者的比例差异（MRD；=最终病理时残留癌症负荷（RCB）≤0.25cm3）。次要终点包括前列腺特异性抗原反应的差异，病理分期,激素治疗后前列腺特异性膜抗原（PSMA）PET/MRI的TNM分期变化。生物标志物（前列腺活检的免疫组织化学染色[PTEN，ERG,Ki67,P53,GR,和PSMA]和PSMAPET/MRI衍生的特征）与病理反应（MRD和RCB）相关。
结论：患者随机接受地加瑞利+阿帕鲁胺（n=45）或地加瑞利+匹配安慰剂（n=44）治疗12周，并接受RP治疗。地加瑞克+阿帕鲁胺组患者的MRD发生率明显高于对照组患者（38%vs9.1%；相对危险度[95%置信区间]=4.2[1.5-11]，p=0.002)。在基线前列腺活检中PTEN丢失的患者获得了显著较低的MRD(11%vs43%,p=0.002），并且在最终病理时的RCB高于无PTEN丢失的患者（1.6vs0.40cm3，p<0.0001）。新辅助激素治疗后，PSMAPET估计的肿瘤体积（1.2对2.5ml，MRD患者的p=0.01）和最大标准化摄取值（SUVmax;4.3vs5.7，p=0.007）低于无MRD患者。新辅助治疗后PSMAPET估计体积和PSMAPETSUVmax与最终病理时的RCB显著相关(均p<0.001)。
结论：在高危PCa患者中，与单独使用地加瑞利相比,在RP之前新辅助地加阿帕鲁胺可显著改善病理反应(MRD和RCB).我们的试验结果为新辅助治疗3期试验提供了坚实的假设生成基础，它们能够检测新辅助雄激素受体信号传导抑制剂治疗后长期肿瘤结局的差异。
结果：在这项研究中，我们观察了在前列腺癌根治术前接受地加瑞利加阿帕鲁胺或地加瑞利加配伍安慰剂治疗的高危前列腺癌患者的病理反应差异.我们证明，使用地加瑞克加阿帕鲁胺治疗的患者比使用地加瑞克加匹配安慰剂治疗的患者获得了显着更好的肿瘤反应。需要长期随访以确定改善的病理结果是否转化为更好的肿瘤结果。
