3rd Asia Pacific Prostate Cancer Conference (APPCC), Shanghai, China

Insights into mCRPC in China, Singapore and Indonesia

Prof Rainy Umbas - University of Indonesia, Indonesia (RU)

Prof Narin Voravud - Chulalongkorn University Hospital, Thailand (NV)

Prof Li Ping Xie - Zhejiang University School of Medicine, China (LPX)

RU: Welcome to ACE III programme in Shanghai. I’m Rainy Umbas from Jakarta University of Indonesia. I’m a urologist. I have two famous doctors joining me here. First one is Professor Narin Voravud, a medical oncologist from Thailand. Please introduce you.

NV: I’m a medical oncologist in Chulalongkorn University in Bangkok, Thailand. I’m very pleased to come here to join this television session for the information on the management of prostate cancer which is becoming a common cancer in this region of the world.

RU: And secondly is Professor Li Ping Xie from China. Please introduce yourself.

LPX: Dr Li Ping Xie. I’m a urologist. I come from Hangzhou, the Department of Urology, the First Affiliated Hospital of Zhejiang University, China.

RU: Thank you very much. So we will start with our discussion today. The first question here is, what are the current local treatment choices in your country in the mCRPC? Maybe Professor Xie, you can answer this?

LPX: Yes, it’s a good question as, you know, metastatic castration-resistant prostate cancer in China is a big problem, you know, because in China we haven’t carried out the PSA screen programme, so about… for our initial cases 68% are metastatic prostate cancer, so after about the median time, about 14 to 30, three months, the patient will develop mCRPC. And in China now in the moment the treatment choices for mCRPC is first we will keep the patient serum testosterone level at castration level, and second we will try to add anti-androgen.

And third we will, for those who has got anti-androgen and/or the CIB we will try the anti-androgen withdrawal syndrome, yes, if the patient have this effect, and also we will try to switch them to another second-line anti-androgen therapies. And of course if all these don’t affect, we will try chemotherapy. In China, docetaxel, this drug we have, and also we have cabazitaxel, and beside this we can also have, to give the patient the bisphosphonates and also some patients, we can give them some radiotherapy and something like this.

RU: Thank you very much. Yes, I think it’s interesting that we know that in Asia the incidence of prostate cancer is increasing. However, we still have a problem here. The problem that most of our patients are coming in the later states of the disease, like you already mentioned that more than 60% are diagnosed with metastasis already. I think we have to urge all of the urologists and medical practitioners in Asia especially to work harder to find prostate cancer in the earlier states in the future. So we have a second question for you.

You already mentioned that you gave certain treatment modalities for the patients with CRPCs. How do these policies differ from the AUA or the European guidelines or even with the Chinese Urological Association guidelines itself?

LPX: Yes, it’s also a good question. I think it’s, in principle it’s similar, but the difference is some new agents in China now are not available. For example, abiraterone may be in this year, in August or September we will have. But enzalutamide or orteronel, we don’t have this, and sipuleucel-T, also we have, we don’t have this.

RU: So I think this is a problem of logistic throughout China because I believe that as a big country it must be difficult for the government or the health authorities here to provide every kind of medical treatment for all of the patients here. That’s understandable. But I think once again we as professionals, we maybe have to talk to our government, how that we can provide these new agents as to help our patients, then maybe or hopefully we can give better care to them. Okay, we will switch. Another question now. Should we now be treating the metastasis RPCs differently in Asia or globally based on the guidelines or clinical data that we have? I will ask Professor Voravud to answer this question, please.

NV: I think it’s very important that we treat the patient according to the best evidence that we have. Fortunately, we have many phase 3 mature data confirm that we can increase the overall survival of the patient, which is the ultimate goal in treating cancer patients. We have heard the bad news that we have more and more prostate cancer presenting at advanced stage because we don’t have a very good screening programme. Fortunately, we have many new technology and agents available for the treating of patients because based on the evidence based  medicine from the phase three study, and that’s leading to the guideline, the AUA guideline, the EUA guideline, and as well as the NCCN and CUA guideline, and that is based on the evidence base.

So it is important to treat the patient according to the international standard guidelines, even though there is no local data. That thing needs to be general because the patient cannot wait. We have to wait until we get a mature phase four study in every country, including Asia, so that we know that it is safe and effective the real life practice. But for the time being, once we get a phase three study the patient cannot wait. The time is running out. If we do the, delay treatment, we do not give them effective treatment according to evidence base that we have.

I think it’s very important to treat according to the international standard guidelines.

RU: Thank you very much. I think, yes, it is interesting that in every centre that we should follow the guidelines. Of course this will be based by the evidence, and I would like to suggest our colleagues that once you gave your patient for a certain treatment modality, then we have to go with the follow-up because this is important. And how you can evaluate the effectiveness of this new treatment and then later on hopefully in Asia we will collect our data, because I believe there must be some difference about the results comparing the Western world experience towards Asian experience.

Because we know also from the results from the prostatectomies series, from the hormonal treatment disease treatment policies that there are some differences here. You already mentioned that in Thailand you already start to treat the patients based on the guidelines. Can you explain to us in the last ten years about the evolvement of the treatment modalities, because we know that maybe until early 2000 we have only one taxane modality as our treatment for the CRPC cases, please?

NV: In 2004 Ian Tannock from Canada has already demonstrated the first chemotherapy to be effective for the treatment of metastatic castration-resistant prostate cancer, but after that we have nothing at all, until a few years later we have more and more agents. There’s an evolution, which is good news for the prostate cancer patients. We have so many agents to be choose at this time and that becomes a problem for the doctor, general practitioner, urologist, oncologist because we have too many products. We have those in the phase three study showing that the new product is effective.

For example, after the taxane they did a study, tried to get prostate cancer cell, tried to test the new taxane, and we come up with cabazitaxel. And the studies show that the patients who have the docetaxel failure, they still respond to the cabazitaxel in terms of increasing survival. At the same time, as we know that prostate cancer is a disease of elderly patients, so the elderly patient is… they’re not suitable for chemotherapy, so the best way to go for the non-toxic cytostatic agent like endocrine treatment.

And the data showing that the prostate cancer, even though that seems to be resist to the treatment, if they check for the androgen receptor or the androgen production, it’s still inside of the cancer cell. In other words, the prostate cancer always responds with the androgen inhibition, no matter the clinical resistance. So there are many new technologies try to find out what is the best way to suppress the androgen. So there are two ways to do that. They first need to suppress the androgen synthesis, so we have a drug called abiraterone made from England that again suppresses the synthesis of the androgen outside, inside of the tumour cells.

And secondly, the kind of blockers of the androgen receptor which is the enzalutamide. But both of the drugs, that’s already been approved in many countries. But in Asia Pacific abiraterone has been approved in many countries, but enzalutamide will be approved in Thailand in the next three years. Both of them are very good. That’s the second evolution. The chemo, the second line chemotherapy, we have the hormonal treatment blocking, the androgen synthesis, the androgen receptor, and the third innovative treatment is very fancy thing; that is a cancer vaccine.

Nobody believes the cancer vaccine can treat cancer and this is the very first… I think it’s the first therapeutic cancer vaccine in the world, published about four years ago, showing that the dendritic cell-based prostate cancer vaccine can increase survival in patients who is not symptomatic. So we have a vaccine, we have endocrine treatment, we have chemotherapy, and lastly we have the radiopharmaceutical agent called radium-223 which show increased survival for both symptomatic, asymptomatic patients, and half of the study of these patients, they are chemo naïve.

In other words, they never received any chemo. They still respond to the radium-223 which is a non-toxic treatment and increasing in survival. So we have at least four modalities to treat prostate cancer patients and the radium-223 has already been registered in Thailand, will be approved in Thailand very soon. Abiraterone, approved already one year. Cabazitaxel, one year ago. And enzalutamide in three years’ time. So we, as a clinician, we have more and more options to treat prostate cancer patients in the past ten years. That’s very good news for prostate cancer patients.

RU: Thank you very much. So it means that in the last ten years actually we have only one, if I can say only one agent to treat the CRPC, but now after ten years suddenly we have more than four or five new agents here that works in different pathway to treat CRPCs. And I’m very glad that these new agents also already coming to Asia and we as a clinician in Asia treating the prostate cancer patients in their later states, especially these RPC, also involved in the trials I believe, also now in some countries it’s already available. Now could you explain more about the newer agents such as the cabazitaxel or enzalutamide and abiraterone acetate, because I believe that they work in different pathway?

NV: This is a very interesting question because we learn more about prostate cancer. One way to overcome the disease is to know the biology and to personalise the cancer treatment. Unfortunately, at this time we cannot select the best target in every patient. In other words, we cannot predict which patient will respond to the treatment. The chemotherapy still works regardless of the target. That’s why cabazitaxel comes as a second-line treatment. It will kill all the cancer cells, but it is non-specific. It has a lot of side-effects.

The cabazitaxel is good, but it is too toxic. The dose modification or GCF profirention is important. And for elderly patients, if they get chemotherapy, most of them, you ask them, they said, no chemo. I don’t want it. I don’t like it because it’s too toxic. Then you have another option, is endocrine treatment. The endocrine treatment, firstly the abiraterone the patients who have failed docetaxel, but at this time there is a new study called COU-302 in asymptomatic, mildly asymptomatic metastatic castration which is prostate cancer. It shows survival benefits, trends to have survival benefits.

We don’t… we need more metadata to look at, but the primary endpoint, radiologic progression-free survival, it showed that it can stop the growth of the tumour. Once the tumour stopped growing, then we can decrease the symptoms of the patient. We can increase the quality of life according to the most recent publications. And, interestingly, the study last year showing that the Gleason Score also predicts the effectiveness of abiraterone in the first-line treatment, so we have more and more parameters to use, we have more agents to use.

And enzalutamide, the story of enzalutamide is very interesting as well because it blocked the androgen receptor which is the common pathway, the final pathway of the disease. Sometimes when you block the synthesis you cannot completely block, but when it escapes to that pathway the DESH increasing, the high, the dihydro-epi and steroids is increasing, indicating that abiraterone doesn’t completely work. Then we have, we can block the androgen receptor. So the clinician has more options to use the drug effectively and safely. The enzalutamide is interesting.

They follow the abiraterone in the same way. They start, look at the patient who receives the docetaxel first and is shown to increase survival as well, and after that they switch to the first-line treatment. Chemo naïve, the patient who never received chemotherapy, the patient want to get some endocrine, non-toxic treatment; they think about enzalutamide. And through the randomisation study, the PREVAIL study show that enzalutamide also effective in docetaxel naïve patients. So at this time it’s very good news for prostate cancer patients.

We have so many products to be used. Some of the agents, they have metadata. Like abiraterone, we are in mature phase three study in COU-301 and COU-302 that can be used for chemo naïve and docetaxel failure. The evidence base is different and we also have enzalutamide, which is another endocrine treatment, to be used for the treatment of metastatic prostate cancer. But once we have too many agents the problem is that, how to sequence in the clinic effectively? Which agent should be used first? Which should be used second? I think there are, in my opinion, there are five ways to do that.

First is the efficacy; which one is better? Second, the safety. For elderly patients endocrine treatment is a preferable treatment. And thirdly, the cost or the reimbursement issue. And fourthly, it’s the patient’s choice. Maybe if you are clinician asking, what do you want, the chemo or endocrine treatment? If I am a patient I would have said, of course I will go for endocrine treatment because the chemo might be too toxic for me or for my father because they are elderly patients. And lastly, it’s physician preference which depends on three things; the knowledge skill, the attitude, and the experience.

These three things will make up the clinician to select which will be the best treatment. But it’s very important to give the patient every available agent so that the survival will be increasing much more than what happened in the past. We can achieve many good success if we do the treatment according to the guidelines, as we discussed before.

RU: Thank you very much. I think it is now important for us here as a clinician that we cannot work by our self anymore because the disease is too complex and we have more and more new agents to treat this disease, as already mentioned by Professor Voravud, that we have certain drugs working in the endocrine line and other drugs works for the, specifically for the, let’s say as vaccines, and other drugs works on the cells itself. So I think it’s important that we have to work together as a clinician that, what we call the multidiscipline approach to our patient so we know when that we have to start certain drugs and which drug will be more suitable for the patient.

For instance, you mentioned about the elderly, because here in Asia we are facing more and more older people here and I believe that in the future we’ll have more cases of CRPCs, let’s say in their 70s or maybe in the early 80s, then we have to prepare for this. And also the side-effects of the drugs; some side-effects, as already mentioned, will of course make a problem in the haematological life of the patients, let’s say low leucocytes or nitrophinies, that we need to give proper treatment which should be in the multidiscipline approach. I think this is a very important issue nowadays in Asia.

We cannot work by our self, but we have to join our force, then hopefully we can fight, we can help our patients better in the future. As already mentioned by Professor Voravud, I will ask Professor Xie that, how about the new agents like already mentioned, the cabazitaxel or the enzalutamide, abiraterone acetate use in China? Could you please explain to us?

LPX: Yes, I quite agree with what you have said. The most effective treatment depends on multidisciplinary team efforts and I think it’s… in the next few years in China I think we will have, first we will have abiraterone and then I think we will have enzalutamide and orteronel and maybe sipuleucel-T and also we can have other agent like Denosumab etc.

RU: Yes, I can add that in Indonesia we, at this moment we have abiraterone acetate. Hopefully it will be recognised by the authority this year and it could be used for more, to help more cases. Now we are still in the clinical study towards having the proposal by the authority. Then hopefully they will accept that as, register that in Indonesia. I think besides that we need also to, once again, to urge our colleagues, find the patient as early as possible, so they have to work hard. We have to work together to fight these cases, especially in the later stage, because it’s not only getting the treatment.

We need also to look to the patient as a whole. We need to maybe sometimes give a palliative treatment against the pain and we have to explain to the family members what will happen if we give certain drugs, what is the side-effects, how can we overcome the side-effects, and I think also we have to give a certain treatment on the, let’s say on the anxiety of the patient himself because he’s thinking if he look at his BSA which is still increasing, then he will ask himself, what will happen to me?

Then of course maybe we need somebody to make him calm and we have to reassure them that, okay, we still try to help you, please stay in the treatment, what that the, as the decision by the physician. I think we will conclude our discussion today and we know that in the last or in the last couple of years only we have very huge changing in the treatment, especially for the metastasis CRPCs in prostate cancer, and now we have too many, or not too many, we have many drugs that we can use to cure or to treat our patients. So we will thank you all for joining us here in Shanghai. Thank you very much.