编者按：在前列腺癌的治疗路径中，生化复发（BCR）是一个关键的转折点。特别是对于PSA倍增时间较短的高危BCR患者，如何延缓疾病进展并改善总生存期（OS）一直是临床关注的焦点。在近期举行的第十五届上海泌尿肿瘤学术大会上，肿瘤瞭望-泌尿时讯特邀美国西达赛奈医学中心Stephen J.Freedland教授，就EMBARK研究的设计初衷、临床获益以及高危BCR患者的个体化治疗方案进行深度解析。

 

Stephen J.Freedland教授：EMBARK研究是一项全球多中心、随机、对照的III期临床试验，旨在评估恩扎卢胺在高危生化复发（BCR）患者中的应用策略。基于恩扎卢胺在转移性前列腺癌领域已证实的生存获益，我们探索其能否“前移”至非转移性阶段。研究入组了常规影像学检查（CT或骨扫描）未发现转移病灶，但具有高危生化复发风险（定义为PSA倍增时间≤9个月）的患者。

 

患者被随机分配至三组：恩扎卢胺联合雄激素剥夺疗法（ADT）组、单纯ADT组、以及恩扎卢胺单药治疗组，这是ARPI药物首次在III期临床试验中作为单药进行评估。研究采用了特殊的“间歇治疗策略”：初始治疗9个月后，若PSA降至0.2 ng/mL以下则停药；待PSA重新升高后，再恢复原分配方案的治疗。

 

与单纯ADT组相比，恩扎卢胺联合治疗显著延迟了疾病进展。其主要终点无转移生存期（MFS）风险降低了58%，这一结果非常显著。更具里程碑意义的是，联合方案导致了全因死亡风险降低超过40%，这种在III期临床试验中取得的OS获益在非转移阶段是前所未有的。相比单纯ADT组，恩扎卢胺单药组在延迟疾病进展（转移或死亡）方面表现出37%的风险降低。虽然OS的风险比（HR）为0.83，显示出改善趋势，但未达到统计学显著性。

 

EMBARK研究的结果为高危BCR前列腺癌患者提供了强有力的证据支持，尤其是恩扎卢胺联合ADT方案在MFS和OS上的双重突破，确立了强化内分泌治疗在该阶段的地位。在临床实践中，临床医生应根据患者的风险分层、生活质量诉求及耐受性，制定精细化的个体化方案，并在治疗全程中加强对副作用的预警与管理。

 

Professor Stephen J.Freedland:The EMBARK study(NCT02314442)is a global，multicenter，randomized Phase III clinical trial designed to evaluate the application of enzalutamide in patients with high-risk biochemical recurrence(BCR).

 

Study Background and Inclusion Criteria:Based on the proven survival benefits of enzalutamide in metastatic prostate cancer，we explored whether its use could be moved"upstream"to the non-metastatic stage.The study enrolled patients with no metastatic lesions detected by conventional imaging(CT or bone scan)but who exhibited a high risk of biochemical recurrence，defined as a PSA doubling time(PSADT)≤9 months.

 

Study Design:Patients were randomized into three arms:enzalutamide plus androgen deprivation therapy(ADT)，ADT alone，and enzalutamide monotherapy(marking the first time an ARPI has been evaluated as a monotherapy in a Phase III trial).A unique"intermittent treatment strategy"was employed:after 9 months of initial treatment，if PSA dropped below 0.2 ng/mL，treatment was suspended;treatment resumed with the original assigned regimen only when PSA levels rose again.

 

Key Efficacy Data:Combination Group(Enzalutamide+ADT):Compared to ADT alone，the combination therapy significantly delayed disease progression.The primary endpoint，Metastasis-Free Survival(MFS)，showed a 58%reduction in risk，a highly significant result.More importantly，the combination regimen led to a reduction in the risk of all-cause death by over 40%.Such a significant OS benefit in a Phase III trial for the non-metastatic stage is unprecedented.

 

Monotherapy Group(Enzalutamide alone):Compared to ADT alone，the monotherapy group showed a 37%reduction in the risk of disease progression(metastasis or death).While the Hazard Ratio(HR)for OS was 0.83，indicating a positive trend，it did not reach statistical significance.

 

The EMBARK results provide robust evidence for the management of high-risk BCR prostate cancer.Specifically，the dual breakthrough in MFS and OS achieved by the enzalutamide plus ADT regimen establishes the role of intensified endocrine therapy in this disease stage.In clinical practice，physicians should develop refined，individualized plans based on a patient’s risk stratification，quality-of-life expectations，and tolerability，while maintaining vigilant monitoring and management of adverse effects throughout the treatment course.

 

Stephen J.Freedland教授：通过综合分析EMBARK、PRESTO以及STAMPEDE等研究，我们可以得出几个对临床实践至关重要的结论：

 

1.ARPI并非“多多益善”：多项研究表明，同时联合使用两种雄激素受体通路抑制剂（ARPI）并不优于单一ARPI。这种联合只会增加毒性，而无额外的抗癌获益。因此，临床上不建议联合两种ARPI。

 

2.强化治疗的持续性与一致性：PRESTO研究中，患者接受52周治疗后停药，重启治疗时仅使用单纯ADT。但在EMBARK研究中，重启治疗时仍采用初始的强化方案（如恩扎卢胺+ADT）。PRESTO未观察到明显的MFS获益，而EMBARK看到了显著的生存获益。这启示我们，不仅初始治疗要强化，生化进展后重启的治疗也需要维持相同的强化方案。

 

3.研究提供了个体化治疗选择。多数高危患者推荐使用联合强化治疗（ARPI+ADT），以获得最佳的生存保护。对于部分疾病侵袭性相对较低（虽属高危但不属于极高危）且高度重视性功能保护的患者，恩扎卢胺单药治疗是一个可行的替代选择。

 

Professor Stephen J.Freedland:By synthesizing findings from the EMBARK，PRESTO，and STAMPEDE trials，we can derive several conclusions vital to clinical practice:

 

1.ARPIs are not"the more，the better":Multiple studies indicate that combining two different androgen receptor pathway inhibitors(ARPIs)simultaneously is not superior to using a single ARPI.Such combinations only increase toxicity without providing additional oncological benefits.Therefore，dual ARPI therapy is not recommended.

 

2.Continuity and Consistency of Intensified Therapy:In the PRESTO study，patients stopped treatment after 52 weeks and restarted with ADT monotherapy upon progression.However，in EMBARK，patients who restarted treatment returned to their original intensified regimen(e.g.，enzalutamide+ADT).While PRESTO did not observe a significant MFS benefit，EMBARK demonstrated clear survival advantages.This suggests that not only should the initial treatment be intensified，but the regimen used upon restart after biochemical progression should also maintain the same level of intensification.

 

3.Individualized Selection:Most High-Risk Patients:Intensified combination therapy(ARPI+ADT)is recommended to achieve optimal survival protection.Specific Populations:For patients with relatively less aggressive disease(high-risk but not"ultra-high"risk)who highly prioritize the preservation of sexual function，enzalutamide monotherapy serves as a viable alternative.

 

Stephen J.Freedland教授：随着ARPI药物应用窗口的前移，患者用药时间延长，长期副作用的管理变得尤为重要。恩扎卢胺单药治疗的特殊副作用：单药治疗的优势在于潮热症状明显减少，但乳房发育（乳腺增生）非常常见。通常会在治疗前对乳房进行预防性放射治疗，或给予他莫昔芬。关于他莫昔芬的剂量，临床上从每天10mg到每周10mg均有尝试，目前尚无公认的最佳标准，但医生必须预先考虑并管理这一问题。

 

恩扎卢胺联合ADT本质上可以看作是“增强版的ADT”，因此副作用谱系与ADT相似，包括疲劳、潮热等，但程度可能更深。基础管理方面，强调生活方式干预。确保患者饮食健康、坚持运动并保证充足睡眠。良好的运动能显著降低跌倒、骨折和疲劳的风险。虽然绝大多数患者能够耐受全剂量治疗，但如果生活方式干预效果不佳，医生应果断进行剂量调整，以平衡疗效与生活质量。

 

Professor Stephen J.Freedland:As the window for ARPI application moves earlier in the disease course，patients remain on treatment for longer durations，making the management of long-term side effects particularly critical.

 

Enzalutamide Monotherapy Specifics:The advantage of monotherapy is a significant reduction in hot flashes;however，gynecomastia(breast enlargement)is very common.Management:We typically consider prophylactic breast irradiation before starting treatment or the administration of Tamoxifen.Regarding Tamoxifen dosing，clinical practices vary from 10 mg daily to 10 mg weekly;while there is no consensus on the"optimal"standard，clinicians must proactively address this issue.

 

Combination Therapy Side Effects:Enzalutamide plus ADT can essentially be viewed as"intensified ADT".Consequently，the side effect profile is similar to ADT alone—including fatigue and hot flashes—though the severity may be more pronounced.Management:Lifestyle interventions are emphasized.Ensure patients maintain a healthy diet，adhere to regular exercise，and get sufficient sleep.Proper exercise can significantly reduce the risks of falls，fractures，and fatigue.While the vast majority of patients can tolerate full-dose therapy，clinicians should not hesitate to implement dose adjustments if lifestyle interventions are insufficient to balance efficacy with quality of life.