Oncology Frontier: Can you tell us about advances in treatment for advanced prostate cancer?

　　《肿瘤瞭望》：您能向大家介绍一下晚期前列腺癌的治疗进展吗？

　　Dr de Bono: For the last five years， we have made major advances in treating advanced prostate cancer with several new drugs being available. Now our armamentarium for treating this disease includes docetaxel， cabazitaxel， abiraterone and enzalutamide as well as other drugs becoming available that can further impact treatment. Clearly， castration remains a very important treatment modality and for patients with advanced disease， hormonal therapy with the LHRH analogs is really key. When patients progress on castration， adding drugs like abiraterone or enzalutamide clearly improves survival both in the pre-chemotherapy and post-chemotherapy space. At present， based on the clinical data from the 302 and PREVAIL trials， abiraterone or enzalutamide can be given to patients with metastatic disease who are progressing on castration alone. In this patient population， we know we can improve survival and quality of life， but clearly these drugs should be given with castration. The bigger challenge is to know when to stop these drugs. I think it is easier to know when to start them. At present we have no data for using these drugs in patients without metastasis and zero disease although I suspect that eventually through trials like the STAMPEDE trial (which will report in the not-too-distant future)， it is likely we will get data that could show that drugs like abiraterone， enzalutamide or even a combination could be valuable from the outset from diagnosis. But at present these drugs should be used primarily in patients with metastatic disease.

　　de Bono博士：在过去五年中，治疗晚期前列腺癌的几种新药取得了重大进展，现在治疗这种疾病的药物包括多西他赛、卡巴他赛、阿比特龙、恩杂鲁胺，以及一些其他可以进一步影响治疗的药物。显然，去势治疗对晚期患者仍然是一个非常重要的治疗方式，激素治疗与LHRH类似物也确实是关键。

　　当患者采取了去势治疗，并添加阿比特龙或恩杂鲁胺等药物，无论是在化疗前还是化疗后，都能明显提高生存率。目前，基于302例患者的一项研究显示，对于仅采用去势治疗的转移性患者可以给予阿比特龙或恩杂鲁胺治疗，可提高生存率和生活质量，但很明显，这些药物应与去势同步进行。我们面临的更大挑战是要知道何时停止使用这些药物，但我认为知道什么时候开始使用这些药物更容易一些。目前我们缺乏未发生转移的以及无病患者使用这些药物的临床数据，虽然我知道，通过STAMPEDE试验及类似研究（这即将在不远的未来向大家报告），很可能我们会得到一些数据，能证明像阿比特龙、恩杂鲁胺，甚至药物组合从诊断开始就有一定的价值。但是，目前这些药物主要还是用于治疗转移性疾病。

　　Oncology Frontier: When is the best time to start chemotherapy and how will that help prolong progression-free survival?

　　《肿瘤瞭望》：什么时候开始化疗是最佳时间，这将如何有助于延长无进展生存期呢？

　　Dr de Bono: Chemotherapy utilization， until very recently， has been reserved for patients with castration-resistant disease at progression on hormonal therapy. There is absolutely no doubt that docetaxel chemotherapy should be given to most patients unless they refuse chemotherapy or they are very unfit with a poor performance status. Drugs like docetaxel should be given to most patients who are progressing on hormonal therapy with metastatic disease after castration and abiraterone， for example， or castration and enzalutamide. At that progression point in metastatic patients， particularly if they are symptomatic but also increasingly if they are asymptomatic， we should give these patients docetaxel. It improves quality of life and survival. Emerging data from the CHARTER trial would suggest that if we actually give chemotherapy earlier， the benefits may be larger. I think what CHARTER has definitely taught us is that we should be giving more chemotherapy. It concerns me that， currently in the Western world， only half of advanced prostate cancer patients are getting chemotherapy. I think that is a failure and we are failing many of our patients. However， the CHARTER data do suggest (and perhaps could be said to be compelling) that even at diagnosis if a patient is presented with metastatic disease at the time of diagnosis (and this is a significant proportion of our prostate cancer patients with metastatic disease)， then the use of docetaxel can improve survival even more if given from the outset. The concern is that the CHARTER trial data are contradictory to the results from the GETUG-15 French trial which was a smaller but similar trial which showed that docetaxel early on can improve progression-free survival but not overall survival. CHARTER showed that it could increase both PFS and overall survival. So concerns remain. Are these CHARTER data bone fide? Will they be confirmed by further trials? My recommendation to people treating advanced prostate cancer is give more docetaxel and give it earlier. If a patient and particularly a young patient with a good performance status presents with metastatic disease at diagnosis， discuss docetaxel with that patient. But I don’t think at present and certainly in my practice， I would definitively recommend to that patient that they must get docetaxel.

　　de Bono博士：直到最近，化疗都是用于接受激素治疗去势后进展的患者。毫无疑问，多西他赛适用于大多数患者，除非患者拒绝化疗或身体机能较差。一些药物，例如多西他赛，适用于激素治疗进展的患者，他们大多在去势治疗及阿比特龙治疗后发生转移，或者去势治疗并使用恩杂鲁胺。发生转移的患者可能会出现一些症状，但越来越多的情况是，如果患者无症状，我们也应该给予多西他赛，它能够提高生活质量及生存期。CHARTER试验的最新数据表明，如果化疗开始得更早，获益可能会更大，我想CHARTER试验明确告诉我们的是，我们应该更多的给予化疗。令我担忧的是，目前在西方世界，只有一半的晚期前列腺癌患者在接受化疗，我认为这是一个失败，我们失去了很多的患者。CHARTER试验的数据表明（也许可以说是引人注目的），即使在诊断时患者出现转移性疾病（前列腺癌患者的转移比例很高），如果从开始就给予多西他赛就可以提高生存期。

　　值得关注的是，CHARTER试验的数据与GETUG-15法国试验是矛盾的，后者样本量较小但是相同的试验，它表明多西他赛仅可以改善无进展生存期，但不是总生存期，而CHARTER试验的结果是同时提高无进展生存期和总生存期，所以担忧依然存在。CHARTER试验的数据是真实的吗？是否需要通过进一步试验来证实？我建议治疗晚期前列腺癌时更多、更早地使用多西他赛，特别是年轻的患者，在诊断时发现转移，具有良好的身体状态，可以与他讨论使用多西他赛，但我不认为目前在我的实践中，我会明确地推荐患者必须使用多西他赛。

　　Oncology Frontier: For patients with early prostate cancer， will timely castration prolong their survival?

　　《肿瘤瞭望》：对于早期前列腺癌的患者，及时去势治疗是否可以延长他们的生存期？

　　Dr de Bono: If a patient has advanced prostate cancer， I think that castration is required to improve survival which is something we clearly have to do for our patients. For patients with a lower Gleason score， let’s say 6， with low risk disease， there is increasing evidence that these patients should be managed by active surveillance and not radical treatment. It is our conviction that many patients are being overtreated and I would strongly recommend that for patients with low volume disease and low risk disease (Gleason score 6) that active surveillance should be the standard of care. In patients with higher risk locally advanced disease， we have clear evidence that castration and hormonal therapy can improve cure rates in conjunction with radical local therapy. So that must be deemed to be the standard of care.

　　de Bono博士：如果患者是晚期前列腺癌，我认为去势治疗是提高生存期的方法，这显然是我们必须做的。但对于Gleason评分较低的患者，例如6分，属于低风险疾病，越来越多的证据表明，这些患者应积极监测，而不是激进的治疗。我们的想法是，许多患者被过度治疗，我强烈建议病灶小的和低风险疾病（Gleason评分6分）的患者把积极监测作为标准。对于高风险的局部晚期患者，我们有明确的证据表明，去势治疗、激素治疗与根治性局部治疗相结合可以提高治愈率，必须作为治疗标准。

　　Oncology Frontier: Studies indicate that androgen deprivation therapy (ADT) initial combination therapy with docetaxel chemotherapy can prolong the overall survival of metastatic prostate cancer. Are there any new drug combinations for the treatment of prostate cancer?

　　《肿瘤瞭望》：研究表明ADT联合多西他赛可以延长转移性前列腺癌的总生存期，治疗前列腺癌是否有新的药物组合？

　　Dr de Bono: That’s an important question. Firstly let me discuss the emerging data from the field. We， and others， have confirmed that if a patient progresses on abiraterone， the antitumor activity of enzalutamide is at best modest. Conversely， if a patient has had enzalutamide and has progressed， the antitumor activity of abiraterone post enzalutamide is modest. The data that are emerging from Antonarakis and Jun Luo at Johns Hopkins published in the New England Journal of Medicine just a few weeks ago， indicate that a common resistance mechanism to these drugs is the generation in these tumors of increased activation of splicing particularly of the androgen receptor (AR). That generates androgen receptor splice variants that are considerably active. They don’t need hormones to be activated. So clearly， these cancers when stressed by hormonal deprivation with abiraterone and enzalutamide activate this oversplicing program that is probably an evolutionary conserved resistance mechanism for the cells to survive. These data don’t prove the splicing of AR is the cause of resistance. There may be other proteins that are being spliced that are also causal in that resistance mechanism. However these data would suggest that we need better drugs that can impact cancers that express AR splice variants. We， and others， have also published data on cabazitaxel. Unlike abiraterone or enzalutamide， in patients who have already had abiraterone or enzalutamide， it remains highly active with a 40% response rate. So my recommendation， if you can， is if your patient has had abiraterone or enzalutamide and docetaxel， the next best treatment is probably cabazitaxel. I remain concerned that only a small proportion of patients today， maybe about 25-30%， are currently receiving cabazitaxel. This should remain as the treatment of choice as， in my mind， it improves survival and also probably quality of life. With regard to combinations， we are delivering now a number of different trials that are showing very exciting preliminary results in the laboratory. Whether these will translate in the clinic， I don’t know. We are also presenting at this meeting， exciting new data with PARP inhibitors in a subset of advanced prostate cancers. I think that data will eventually improve outcomes from this disease.

　　de Bono博士：首先请让我谈一下该领域最新的数据。我们及其他研究者发现，如果患者使用阿比特龙发生进展，此时使用恩杂鲁胺的抗肿瘤活性是最佳的。相反，如果患者已经使用了恩杂鲁胺并已进展，应用于恩杂鲁胺之后的阿比特龙其抗肿瘤活性很弱。这些是几个星期前约翰霍普金斯大学Antonarakis和罗军公布在《新英格兰医学杂志》的数据，表明这些药物一个共同的耐药机制是增加这些肿瘤中雄激素受体的活性，其产生的雄激素受体的剪接变体相当活跃，不需要激素激活。显然，当使用阿比特龙和恩杂鲁胺时，通过激素剥夺而激活了这些程序，这可能是一种进化上保守的机制，使细胞得以存活。这些数据并不证明雄激素受体是耐药的原因，可能有其他蛋白质剪切片段也是耐药产生的原因。

　　然而，这些数据表明，我们需要更好的药物来影响雄激素受体剪接变异体的表达。我们及其他研究者，也纷纷发表了卡巴他赛的研究数据。不像阿比特龙或恩杂鲁胺，对于已经使用阿比特龙或恩杂鲁胺的患者，卡巴他赛仍然有40%的有效率。所以我的建议是，如果你的患者已经使用阿比特龙、恩杂鲁胺和多西他赛，下一个最好的治疗方法可能是卡巴他赛。而我的担忧是，目前只有一小部分患者，比例为25%~30%在接受卡巴他赛治疗。这应继续作为首选治疗，在我看来，它可以提高生存率和生活质量。至于药物组合，我们现在可以提供一些实验室中得到的令人兴奋的初步结果，但是否能应用于临床仍是未知数。我们在本次会议中也报告了PARP抑制剂治疗晚期前列腺癌的新数据。我认为，这些数据最终会改善这种疾病的结果。

　　Oncology Frontier: What are the factors related to prostate cancer? How do we prevent prostate cancer in our daily lives?

　　《肿瘤瞭望》：与前列腺癌发生有关的因素是什么？我们如何在日常生活中预防前列腺癌的发生呢？

　　Dr de Bono: Increasing evidence would suggest that prostate specific antigen (PSA) screening that has been used extensively particularly in the USA to try and decrease the mortality from this disease， has failed and has resulted in the overtreatment of patients. I think moving forward， targeted screening of high risk populations of patients (for example， patients with a family history or patients with normal germ line DNA SNPs (single nucleotide polymorphisms) which are at-risk inherited genomic changes for which we may be able to do targeted sequencing in people at high risk) to actually minimize the chances of getting lethal prostate cancers. The precise cause of prostate cancer is not fully understood. There is increasing evidence that hormones themselves such as testosterone and estrogen may actually cause the DNA damage that may generate this disease. Also， inflammation in the prostate may be causal here. But because we don’t fully understand what causes the disease， I think much work needs to be done to further understand how we can prevent it. We need better screening methods and it is my conviction that liquid， biopsy or looking at blood tumor DNA may allow us to develop early detection methods that are better than PSA screening.

　　de Bono博士：越来越多的证据表明，前列腺特异抗原（PSA）的筛选已被广泛应用，特别是在美国，来试图减少这种疾病，但是已经失败了，并导致了患者的过度治疗。我认为下一步应该是有针对性地对高危人群检测（例如，筛查有家族史的患者或患者的DNA单核苷酸多态性，即观察有风险的遗传性基因的变化，而我们能够在高危人群中有针对性地测序），减少致死性前列腺癌的发生比例。前列腺癌发生的原因至今未查明，越来越多的证据表明，激素本身，如睾丸激素和雌激素可能会导致DNA损伤继而致病。此外，前列腺炎也可能是原因之一。我们不完全了解是什么原因导致这个疾病，还有许多工作需要进一步开展，来了解我们怎么才能阻止它的发生。我们还需要更好的筛选方法，液体活检或血液肿瘤DNA可以帮助我们找到比PSA筛检更好的早期检测方法。