Triplet Therapy: Entering the Metaverse of Metastatic Hormone-sensitive Prostate Cancer Treatment

三联疗法：进入转移性激素敏感性前列腺癌的治疗领域

背景介绍

Systemic treatment options for patients with metastatic hormone-sensitive prostate cancer (mHSPC) have evolved dramatically in recent years on the basis of clear evidence that treatment intensification at an early stage improves survival and delays progression over androgen deprivation therapy (ADT) alone.  

近年来，转移性激素敏感性前列腺癌（mHSPC）患者的系统性治疗方案发生了巨大的变化，因为有明确的证据表明，与单纯雄激素剥夺治疗（ADT）相比，在早期阶段进行强化治疗更能提高生存率并延缓病情进展。

文献回顾

Initially, evidence supported the use of doublet therapy, with the addition of either docetaxel chemotherapy or one of multiple approved androgen receptor signaling inhibitors (ARSIs), including abiraterone acetate, apalutamide, and enzalutamide, to ADT, each of which provided similar and meaningful clinical benefits in specific trials. Two randomized control trials (RCTs), PEACE-1 and ARASENS, recently compared triplet therapy (docetaxel + ARSI + ADT) to docetaxel + ADT and clearly demonstrated better overall survival (OS) with triplet therapy, making triplet therapy a new standard of care for patients with mHSPC, particularly in high-volume and de novo mHSPC.

最初，有证据支持使用双联疗法，即ADT联合多西他赛化疗或雄激素受体信号抑制剂（ARSI），目前已有多种获批的ARSI，包括醋酸阿比特龙、阿帕鲁胺和恩杂鲁胺，在相关试验中，每一种ARSI都提供了类似的、有意义的临床益处。最近两项随机对照试验（RCT），PEACE-1和ARASENS，比较了三联疗法（多西他赛+ARSI+ADT）和多西他赛+ADT，明确显示接受三联疗法的患者总生存（OS）更优，使三联疗法成为mHSPC患者新的标准疗法，特别对于疾病负荷较高的新发mHSPC患者。

Still, outstanding questions remain as to which patients might benefit most from this further intensification of systemic therapy given the added toxicity and temporary quality-of-life impact of docetaxel, as well as how to apply these results to clinical practice.

然而，由于多西他赛有额外毒性以及暂时会影响生活质量，有些问题仍未解决，比如哪些患者可从这种进一步强化的系统性治疗中获益最大？如何将这些结果应用于临床实践？

In PEACE-1, addition of abiraterone to docetaxel plus ADT significantly improved progression-free survival (PFS) and OS in comparison to docetaxel + ADT alone. In ARASENS, addition of darolutamide to docetaxel plus ADT significantly improved OS. On the basis of these results, darolutamide was recently approved by the US Food and Drug Administration for use in combination with docetaxel and ADT for patients with mHSPC. 

PEACE-1显示，与多西他赛+ADT相比，阿比特龙+多西他赛+ADT可显著改善无进展生存期（PFS）和OS。ARASENS显示，达罗他胺+多西他赛+ADT可显著改善OS。基于这些结果，最近美国食品和药物管理局批准可将达罗他胺与多西他赛和ADT联合使用来治疗mHSPC患者。

In addition to these studies of concurrent ARSI + docetaxel, the registrational trials of enzalutamide and apalutamide allowed some patients to receive prior docetaxel, demonstrating the safety and feasibility of sequential use of these ARSIs after docetaxel in combination with ADT, and clearly showing significant delays in PFS in this subgroup of docetaxel-pretreated men with mHSPC, although an OS benefit was not clear and the trials were not designed or adequately powered to address this question of triple therapy. 

除了这些同时使用ARSI+多西他赛的研究外，关于恩扎鲁胺和阿帕鲁胺的注册试验允许一些患者先接受多西他赛，这些试验证明了在多西他赛治疗后再序贯ARSI联合ADT治疗具有安全性和可行性，并明确显示，在预先接受多西他赛治疗的mHSPC患者亚组中，PFS明显更优，但是OS获益并不明显，而且这些试验的目的并不是研究三联疗法的相关问题，也没有足够把握能解决三联疗法的相关问题。

Identification of patient subgroups most likely to benefit from treatment intensification, specifically the incorporation of docetaxel, is important to individualize treatment decisions and optimize treatment intensification for those men most likely to benefit while minimizing the harms and added costs for those men who do not clearly benefit. 

对于为那些最有可能获益的患者进行个体化治疗并优化强化治疗，同时为那些没有明显获益的患者最大限度地减少危害和成本，重要的是要识别最有可能从强化治疗（特别是联合多西他赛）中获益的患者亚群。

In the phase 3 CHAARTED trial evaluating docetaxel + ADT compared to ADT in mHSPC, patients were stratified by disease volume, with high-volume disease defined as visceral metastases and/or four or more bone metastases, with at least one outside the vertebral column and pelvis. An OS benefit was observed for patients with high-volume disease, whereas no OS benefit was seen for patients with low-volume disease. By contrast, a benefit of ARSI addition to ADT was seen across subgroups stratified by disease volume or risk. 

在比较多西他赛+ADT和单纯ADT治疗mHSPC患者的3期CHAARTED试验中，将患者按疾病负荷分层，疾病负荷较高定义为内脏转移和/或≥四个骨转移，其中至少一个在脊椎骨和骨盆之外。该试验观察到，对于多西他赛+ADT，只有高负荷疾病患者有OS获益，而低负荷疾病患者则没有OS获益。然而对于ARSI+ADT，其他根据疾病负荷或风险对患者进行分层的试验在所有亚组中均观察到获益。

In PEACE-1, patients with high-volume disease according to CHAARTED criteria had significantly better OS, while OS data for patients with low-volume disease were immature and thus any potential OS benefit in this population is not yet clear owing to lower event rates over time. Patients were not stratified and the data have not yet been reported by disease volume in ARASENS for darolutamide outcomes. 

PEACE-1试验显示，高负荷疾病（CHAARTED标准）患者的OS明显更优，而低负荷疾病患者的OS数据尚不成熟，因此，由于事件发生率较低，低负荷疾病患者的潜在OS获益尚不清楚。关于达罗他胺的ARASENS试验没有对患者进行分层，也没有报告在不同疾病负荷的患者中达罗他胺的治疗结局数据。

重点研究

In this issue of European Urology, Yanagisawa et al. report results of a systematic review, meta-analysis, and network meta-analysis (NMA) undertaken to evaluate the outcomes of triplet therapy involving docetaxel + ARSI + ADT and to compare its efficacy with currently available doublet therapies in mHSPC. They identified 11 RCTs comprising 7679 patients, including the previously mentioned trials, for inclusion in their meta-analyses and NMAs.  

在European Urology中，Yanagisawa等人报告了一项系统性回顾、荟萃分析和网络荟萃分析（NMA）的结果，这项研究旨在评估多西他赛+ARSI+ADT三联疗法的结局，并比较三联疗法与目前可用的mHSPC双联疗法的有效性。该研究识别了11项RCT，共7679例患者，包括前面提到的试验，以进行荟萃分析和NMA。

Not surprisingly, they found that triplet therapy resulted in better OS and PFS for patients with mHSPC in comparison to docetaxel + ADT or ARSI + ADT. They used NMAs to rank all treatments and found that for patients with de novo high-volume mHSPC, triplet therapy had the highest likelihood of better OS, while doublet therapy with ARSI + ADT had the highest likelihood of better OS for patients with low-volume disease.

最终发现，与多西他赛+ADT或ARSI+ADT相比，接受三联疗法的mHSPC患者OS和PFS更优。该研究使用NMA对所有治疗方法进行评估，发现对于高负荷新发mHSPC患者，三联疗法的OS益处可能更优，而对于低负荷疾病患者，ARSI+ADT双联疗法的OS益处可能更优。

This study is a timely and comprehensive evaluation of triplet therapy in mHSPC and provides support to conclusions that can be drawn from the individual RCTs. Still, as the authors note, caution is needed to avoid overinterpreting results from an NMA or making statements of individual agent superiority on the basis of the results, particularly given the lack of power for patients with low-volume disease and the heterogeneity of patient eligibility in each trial, as well as the lack of prospective head-to-head pairwise comparisons of individual ARSIs in this setting.

这项研究对mHSPC的三联疗法进行了及时和全面的评估，并为从RCT中得出结论提供了支持。然而，正如该研究作者所指出的，对于低负荷疾病患者，该研究的把握度不够，纳入的每个试验的患者入组资格具有异质性，而且缺乏对各个ARSI的前瞻性头对头配对比较，需要避免过度解读NMA的结果，也不能仅根据此研究的结果就声明某个药剂更优。

NMAs extend the principles of meta-analyses to allow for comparison of more than two treatments in a single analysis using both direct comparisons of interventions within RCTs and indirect comparisons across RCTs obtained via a common reference comparator. The potential of NMAs to allow comparison of treatments across trials is appealing in oncology, with multiple available therapies for a given disease never compared directly to each other in RCTs but often evaluated in RCTs with a common control comparator. Still, the results from this and other NMAs should be interpreted with caution given the heterogeneity of even similar-appearing trial populations and comparators (eg, lumping all ARSIs together as one treatment) and the potential biases that may impact these results. 

NMA扩展了荟萃分析的原则，允许在一次分析中比较两种以上的治疗方法，既可在RCT内直接比较干预措施，也可在各个RCT之间通过共同的比较对象进行间接比较。在肿瘤学中，NMA可以跨试验来比较治疗方法，这是很有吸引力的，因为对于某种疾病的多种可用疗法，从未在RCT中直接对每个疗法进行相互比较，而是经常通过一个共同的比较对象进行评估。然而，即使是看起来相似的试验人群和比较对象（例如，将所有ARSI都归为一种治疗），也都具有异质性，以及可能存在影响NMA结果的偏倚，所以应该谨慎地解释此NMA和其他NMA的结果。

For example, the proportion of patients in each trial may differ by disease volume, prior local therapy, geographic region, post-treatment therapy availability, study time periods, the method for efficacy measurement over time, and tumor or germline genetic alterations, and even the control groups may differ widely in outcomes, including toxicities. Results from NMAs can be hypothesis-generating and help in supporting conclusions from well-designed RCTs, as can be done with the report by Yanagisawa et al, but should not be used to declare the superiority of a specific regimen alone and thus are generally not necessarily practice- or guideline-changing by themselves.

例如，每个试验中的患者比例可能因疾病负荷、先前的局部治疗、地理区域、治疗后疗法的可用性、研究时间段、随时间变化的有效性评估方法以及肿瘤或种系突变而不同，甚至对照组的结局也可能有很大差异，包括毒性。可以根据NMA的结果进行假设，NMA的结果也有助于支持设计良好的RCT的结论，正如Yanagisawa等人的报告一样，但不应该仅根据NMA的结果来宣布某一疗法更优，因此一般来说，NMA本身不一定能改变实践或指南。

Triplet therapy with docetaxel + ARSI + ADT has clearly become a standard of care for patients with mHSPC, particularly for patients with high-volume de novo metastatic disease, but should be considered for all patients in settings in which these treatments are available and affordable (Table 1). It remains incumbent on our collective societies to now make these therapies more available and affordable given that many men with mHSPC remain undertreated in the community and often receive ADT alone. Patients with high-volume de novo metastatic disease are a subgroup of the mHSPC population who generally have aggressive disease at presentation and lower survival reported across trials, warranting aggressive upfront systemic options such as triplet therapy. 

多西他赛+ARSI+ADT的三联疗法显然已经成为mHSPC患者的标准治疗方法，尤其是对于高负荷的新发转移性疾病患者，但在可以获得这些治疗方法且负担得起的情况下，应该考虑对所有患者进行治疗（表1）。考虑到许多mHSPC患者在社区医院内未得到充分的治疗，并且常常只接受ADT治疗，因此我们仍有责任使这些治疗方法更易获得且负担得起。高负荷的新发转移性疾病患者是mHSPC患者群中的一个亚组，他们在就诊时通常具有侵袭性疾病，并且各个试验报告这类患者的生存率较低，因此需要积极的前期系统性治疗方案，如三联疗法。

In contrast, patients with low-volume mHSPC, particularly those with metachronous metastatic disease, generally have more indolent, potentially hormone-responsive disease, and thus the benefit of adding chemotherapy is less clear for this group. Radiation to the prostate is another form of treatment intensification reserved at present for patients with de novo low-volume disease on conventional imaging. Ultimately, for all patients with mHSPC, these treatment decisions are multifaceted and need to factor in quality of life, financial costs, and individual patient factors and preferences in addition to survival differences.

相比之下，低负荷的mHSPC患者，特别是那些有异时性转移性疾病的患者，通常更为惰性、激素反应性疾病，因此对这类患者而言，联合化疗的益处不太明显。前列腺放疗是另一种强化治疗，目前只适用于经常规影像学诊断为新发低负荷疾病的患者。最终，对于mHSPC患者来说，适合他们的治疗决定是不一样的，除了生存率的差异外，还需要考虑生活质量、经济成本以及患者个人因素和偏好。

Table 1 – Recommended treatment approach for metastatic hormone-sensitive prostate cancer according to disease volume on conventional imaging and the timing of metastatic disease development^a

表1-根据常规影像学检查观察到的疾病负荷和转移性疾病发生的时间，推荐的转移性激素敏感性前列腺癌的治疗方法^a

未解之谜

Questions remain as to how best to apply these findings in clinical practice. Whether triplet therapy is superior to an ARSI + ADT doublet has not been addressed in an RCT; however, given the comparable efficacy of docetaxel and ARSIs in the STAMPEDE trial, this is generally assumed. Is concurrent administration of an ARSI such as abiraterone or darolutamide with docetaxel superior to sequential administration with these same agents or enzalutamide or apalutamide? 

关于如何在临床实践中最好地应用这些发现仍然是个问题。三联疗法是否优于ARSI+ADT双联疗法尚未在RCT中进行研究；然而，鉴于STAMPEDE试验中多西他赛和ARSI的有效性相当，一般认为三联疗法优于ARSI+ADT双联疗法。ARSI（如阿比特龙或达罗他胺）与多西他赛同时使用是否优于多西他赛序贯阿比特龙或达罗他胺或恩杂鲁胺或阿帕鲁胺？

Concurrent enzalutamide with docetaxel is not recommended owing to potential drug interactions and added toxicity, as observed in ENZAMET, but sequential use of triplet therapy in all patients or in risk-adapted settings on the basis of early responses to docetaxel/ADT has not been adequately addressed in any trials. How do we incorporate more sensitive imaging modalities such as prostate-specific membrane antigen positron emission tomography/computed tomography into decision-making in the context of these studies that used conventional imaging alone?  

正如在ENZAMET中观察到的那样，由于潜在的药物相互作用和额外的毒性，不建议同时使用恩杂鲁胺和多西他赛，但关于在所有患者中，或基于患者对多西他赛/ADT的早期反应在合适的风险人群中，以序贯的方式使用三联疗法，目前还没有任何试验得到有把握的结论。此外，由于这些研究使用的是常规影像学检查，那么在使用更敏感的影像学检查（如前列腺特异性膜抗原正电子发射断层扫描/计算机断层扫描）进行决策时如何利用这些研究的结果？

Ultimately, identification of better predictive and prognostic biomarkers, whether imaging-based, genotypic, or other patient-specific factors, to help identify patients most in need of and most likely to benefit from aggressive triplet or even potentially quadruplet future therapy are essential to ensure that patients are receiving the best individualized treatments in the context of ever-evolving therapeutic options.

最后，无论是影像学方面、基因型方面，还是其他患者因素方面，识别更好的预测性和预后性生物标志物，以帮助确定最需要和最有可能从积极的三联疗法甚至未来可能的四联疗法中获益的患者，对于确保患者在治疗不断发展的时代中接受最佳的个体化治疗至关重要。

Dzimitrowicz HE, Armstrong AJ. Triplet Therapy: Entering the Metaverse of Metastatic Hormone-sensitive Prostate Cancer Treatment. Eur Urol. 2022 Sep 13:S0302-2838(22)02621-5. doi: 10.1016/j.eururo.2022.08.031. Epub ahead of print. PMID: 36114081.